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Adv Mol and Cell Bio (BCH 6415) > Exam 4 > Flashcards

Exam 4 Flashcards

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1
Q

initiator

A

trans acting enzyme that recog origin sites (cis elements) e load DNA helicases
eukaryote: ORC (origin recognition complex)
e coli: DnaA, recog spec sequence

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2
Q

replicon

A

unit of DNA that is replicated under the control of 1 origin/initiator
E coli have one origin, the whole genome is 1 replicon
human: 30,000-50,000, about 100 kb ea

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3
Q

requirements to initate DNA replication

A

replicator - cis-acting factor, origin of replication, directs initiation of rep, for metazoans, doesn’t have a spec DNA seq
initator - trans-acting factor, specifically recog DNA elements in replicator, binds origin e recruits other replication proteins, ORC in humans

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4
Q

how were origins of replication found in prokaryotes

A

insert a segment of genomic DNA into plasmid w selectable marker > put in cells > grow > select
only those that can start replication will maintain plasmid as the cells grow, will be selected for
where ARS name comes from; autonomously replicating seq

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5
Q

elements of e coli OriC

A

245bp replicator, the single origin in e coli
has DnaA R boxes (protein recog sites for e coli initiator)
has DUE (DNA Unwinding Element, AT rich seq, easier to melt)
has GATC sites (allows re-initation)

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6
Q

elements of yeast s cerevisiae ARS

A

defined replicator / origin sequence - ARSE (Autonomously replicating seq element)
ACS - ARS consensus seq
B1 e B2 - additional Orc binding site, seq not as conserved, B2 is inverted B1
many other yeast e all metazoans do NOT have defined consensus seq

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7
Q

issues defining origins in eukaryotes

A

many origins on 1 chr
only 10-30% of licensed origins fire
broad initation zones
firing at diff stages of S phase (even if synchronize cell)
diff in origin usage at diff stages of dev
no defined consensus seq (most eukaryotes)

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8
Q

method for genome wide mapping of origins in eukaryotes

A

isolate RNA primed nascent strands > 5’ ends of primers will diverge at origin of rep, use sucrose gradient to isolate small (0.5-2kb range), isolate nascent strands, remove DNA w exonuclease > deep seq, line up, see where primers line up
result: localization at origins of G rich regions
(CHIP would only show actively firing origins)

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9
Q

factors affecting activation of metazoan origins of rep

A

Origin Usage: Not all licensed origins fire, some always fire, some more flexible, can vary dep on cell type e cycle
Timing of Origin Activation: some start earlier or later, generally relates to condensation of chr, actively transcribed regions rep before heterochromatin, nuclear organization is imp for timing (TADs)

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10
Q

initiation zones

A

spatial organization of origins; replicons are organized into clusters, ea can have ~5 licensed origins but only 1 will activate

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11
Q

why license so many more origins of replication than fire

A

Lots of origins might help deal w rep stress / difficult areas to rep
may allow activation to be coordinated w transcription
May be bc of rep stress , DNA damage, 2’ struct, transcription

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12
Q

replication domain model

A

Chromatin organized into 3D domains that rep as unit
Chromatin interaction maps correlate w rep timing
Early rep domains located more central, have higher initiation factor conc
Late rep domains located at nuclear periphery, lower initiation factor conc
condensation e 3D structure, not 1 end of chr to other
Rif1 (Rap1-interacting factor 1) regulates replication timing (late)

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13
Q

temporal reg of DNA rep

A

nuclear architecture key feature reg rep timing
majority of protein-coding regions are replicated early
on large scale: conserved in same cell types, within a species, between some species
on small scale: diff within domains dep on cell-type, developmental stage, etc.

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14
Q

why must initiators, and DNA rep, be so tightly regulated

A

whole genome must be rep once and only once
think of regulation of initiation as reg of helicase loading e activation

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15
Q

ORC

A

origin recognition complex - eukaryotic initiator
a six-subunit complex of Orc1 - 6
Orc1- Orc5 are members of the AAA+ family of ATPases, have WH domain that interacts w the subsequent Orc, connect all in ring
consumes ATP to load helicase e bind DNA

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16
Q

phases of eukaryotic DNA rep initation

A

licensing - helicase is loaded, pre-replication complexes, occur during late M e G1 (low CDK)
activation - activate helicases, the two back to back helicases move away from ea other, origins fire, S phase (inc in CDK)

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17
Q

steps in licensing the origin

A

Orc binds > Cdc6 joins > Mcm-Cdt1 is recruited > DNA threaded into ‘Mcm2-5 gate’ > Orc, Cdc6, Cdt1 leave
same thing for a second MCM
results in 2 MCM loaded back to back with N term facing ea other, once activated (CDC45 e GINS added) will move away from ea other
Occurs during low CDK levels
Cdc6 e Cdt1 - helicase loading proteins

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18
Q

steps in helicase activation

A

DDK phos Mcm2-7 on DNA
CDK phos Sld2 & Sld3
Sld2-phos & Sld3-phos form complex w Dpb11
Sld2-phos-Dpb11-Sld3-phos recruit helicase activators – Cdc45 e GINS
helicase goes from encircling dsDNA to ssDNA
N-term of helicases drive into ea other, cause twisting of DNA between them, forms bubbles, cross over ea other, move in opposite directions of fork
active CMG

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19
Q

CDK levels and licensing / activation of helicase

A

CDK level low (G1 phase) > helicase is loaded but not activated
CDK levels high (S, G2, e M) > helicase activated but not loaded
CDK prevents re-rep by phos factors needed for licensing including ORC, Cdc6, Cdt1 > leads to their export from nuc and degradation > NO re-licensing
imp to prevent firing an origin twice, makes sure rep DNA once and only once

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20
Q

initiation of rep in e coli

A

DnaA (initiator) is ATP-dep, makes pos supercoils, causes DUE to unwind
once helicase is loaded can immediate go bc on ssDNA, doesn’t need to be activated (e coli only have one origin)
prevent re-initiation bc parent strand is methylated, blocks re-binding

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21
Q

key diff between eukaryote e e coli DNA replication initation

A

eukaryote - helicase loading e activation in 2 diff steps; helicase is loaded around dsDNA to form pre-RC; DNA is melted during activation stage, then helicase binds ssDNA
e coli - origin binding protein (DnaA) recog origin e melts DNA at origin to create ssDNA; helicases are loaded onto ssDNA ; helicase is active as soon as it is loaded

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22
Q

EBV e KSHV e ORC

A

Both have origin binding proteins (EBNA1 & LANA) that recruit ORC

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23
Q

steps in MMR (overview)

A
  1. Recognition - Identify mismatch
  2. Initiation – Start repair process
  3. Excision – Remove DNA + wrong nucleotide
  4. Resynthesize DNA to replace excised segment
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24
Q

how do e coli differentiate parental from daughter strand

A

GATC seq in e coli is methylated, daughter strand is not immediately methylated, if there is a mismatch then know which is parent / daughter

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25
MMR in e coli (traditional)
mut S FINDS mismatch, undergoes conformational change, dimer of mut L then binds mut L activates mut H, mut H is endonuclease, recog hemi methylated GATC e cleaves UvrD (DNA helicase II) binds e moves 5' to 3' towards mismatch, other strand gets cut by exoVII or RecJ can have large gap between methyl group e mismatch, usually cuts at closest methyl, UvrD know: mut S finds mismatch, mut L activates endonuclease, then DNA is cleaved out
26
e coli mut S
sliding clamp in MMR mut S-ADP slides looking for mismatch > binds mismatch > exchange ADP for ATP > conformational change: longer lifetime on DNA, can bind mut L, still slides randomly diffuse, not driven by ATP hydrolysis works best against common mismatches made by pol, helps dec mut rate
27
exo-free MMR model in e coli
Methyl groups on top strand > mut S recog mismatch e slide away (lots of mutS loaded on, all of them slide away) > helicase binds, nick strand 3’ to 5’ > keeps going until hits another methylation, takes out everything in between
28
what does MMR recog
mismatch base pairs small indels (3-4bps)
29
key difference between e coli MMR enzymes and most others
all but e coli have mut L w endonuc funct > combined mut H (endonuclease) e mut L (activates H) funct nicks depends on stimulation by PCNA (mostly), RFC, e ATP
30
mut S alpha vs mut S beta
mut S alpha recog mispair - binds PCNA at IDCL, has directionality mut S beta recog indels in eukaryotes
31
models for initiation of MMR
translocation - loop forms w mismatch inside sliding - lots of mutS sliding around randomly transactivation - recog e folding to bring two areas together (like enhancers) multi-MLH loading - polymer of mut L until reach nick
32
role of PCNA in MMR
stimulates nicking for mut L alpha can bind mut S alpha orientation defines the new strand (e coli uses methylation) depending on where nick is, PCNA loads and will cause repair to that base
33
methods of strand discrimination in MMR
strand discontinuities - nicks / gaps PCNA retained on DNA - short term 'memory' PCNA retained by mut S alpha - mut S alpha holds it in place, long term 'memory' nicks from OF might help distinguish parent v daughter strand > lagging strand is repaired better / more freq than leading
34
what type of damage does MMR recog
base mismatches indels
35
what type of damage does BER recog
SSBs abasic site, 8-oxoguanine
36
what type of damage does HR recog
DSBs (~80% of DSBs repaired by NHEJ, HR less common)
37
HR repair: timing
limited to S phase e early G2, when 2 sister chr next to ea other, one sister is template for other
38
what type of damage does NHEJ recog
DSBs INTERstrand crosslinks repairs ~80% of DSBs
39
what type of damage does NER recog
bulky adducts INTRAstrand crosslinks
40
characteristics of DSBs
one of the most cytotoxic forms of DNA damage sugar-phosphate backbone is damaged, not clean break, ends are not ligateable until processed often contain 3’ phosphate or phosphoglycolate needs a 5’ phosphate and 3’OH for ligation concentration of radicals nearby most DSBs might be from SSBs that are not repaired
41
causes of DSBs
ionizing radiation (cosmic rays, radioativity) un-repaired SSBs chemicals radiomimetic compounds (used as antibiotic in other countries) ROS topoisomerase inhibitors
42
examples of purposeful DSBs
V(D)J recombination class switching meiosis
43
MRN
causes resection of ends of damaged DNA imp for HR
44
key difference between NHEJ e other DSB repair pathways
NHEJ does NOT use MRN, therefore does not have significant end resection has proteins that protect ends from resection HR needs a lot of homology (100+ nts), NHEJ only needs 0-4nts
45
NHEJ: timing
any stage of cell cycle
46
does NHEJ generate mutations
yes
47
does HR generate mutations
no
48
NHEJ overview
req; microhomology (0-4 nts, more homology = more NHEJ) result: mutations, indels, variation DSB with un-clean ends, could have very diff geometry / uneven ends > Ku70-Ku80 binds ends to protect them > DNA-PKcs-Artemis (nuclease) cuts back nts to get clean ends > pol mu or lambda fills in gaps > ligIV-XRCC4 ligates possible accessory end processing: PNKP and TDP1
49
NHEJ: synapsis
med by Ku70/Ku80, high affinity binds DNA ends blocks end resection interacts / recruits other proteins for NHEJ: PAXX or XLF, which helps make correct geometry Ku70/Ku80 blocks pol mu, when LIG4 binds, blocks Ku's ability to block pol mu > pol mu can now bind
50
NHEJ: pol mu dep synapsis
can bind instead of Ku70/Ku80, if Ku is there first it blocks pol mu can generate close synaptic complex e add (a few) nts by templating off opposite strand Ku70/Ku80 is more common pol mu is also imp in Ku mediated synapsis, or can do directly (above)
51
NHEJ: end-processing nuclease
med by DNA-PKcs e Artemis DNA-PKcs - DNA dep protein kinase, funct as scaffold e activates Artemis Artemis - endonuclease e 5' exonuclease > processes ends for ligation, has limited excision, cannot completely remove 3' end of flap (if present)
52
Artemis funct
req for end resection in NHEJ endonuclease e 5' exonuclease > processes ends for ligation, has limited excision, cannot completely remove 3' end of flap (if present)
53
NHEJ: end-processing polymerases
pol mu can add DNA untemplated, can use 3' overhang as template (normal pol cannot), can add to blunt ends, can fill in gaps held together w 1bp of homology > make microhomology does NOT have as high fidelity as rep pol, active site is more open, can cause mut pol lambda requires (minor) templating TdT in V(D)J, can add DNA untemplated
54
pol mu v pol lambda
incompatible ends (no homology, or blunt ends) req pol mu pol mu can add to blunt ends, create microhomology pol lambda is not sufficient
55
NHEJ: ligation
med by DNA LIG4 XRCC4-LIG4 comes as complex, XRCC4 stim ligase activity LIG4 is more promiscuous, can ligate RNA to DNA (other pathways have to go back e fix)
56
NHEJ: accessory proteins
PNKP: adds 5' phos to 5'OH, removes 3' phos TDP1: removes 3' phosphoglycolates, other enzymes (like Artemis) can make up for lack of TDP1 by removing whole nts
57
iterative processing in NHEJ
cleave > add > cleave > add > cleave etc until create microhomology can result in insertions, deletions, or both same seq of DNA is not fixed w same end product, random addition / excision
58
BER overview
Recog: damage recog e base removal by DNA glycosylase removal: - cleavage of abasic site by APE1 OR - cleavage e end processing by bDG (removes wrong base but cuts wrong side), still needs APE1 to process end repair 1: - 'short patch' (1nt) gap filling e removal of abasic nt by pol beta > ligation by XRCC1-LIG3 OR repair 2: - 'long patch' gap filling by pol beta e removal of flap by FEN1 > ligation by LIG1
59
BER: DNA glycosylase
many type, recog diff types of damage recog damage by scanning e base flipping (can only flip out bases w weak (incorrect) bps some only cleave base from sugar (monofunctional, mDG), some cleave base from sugar AND create SSB in backbone (bifunctional, bDG)
60
BER: removal of abasic site
APE1 - cuts DNA backbone 5' of abasic site, processes ends cleaved by bDG, has proofreading for DNA pol errors
61
BER: polymerase
DNA pol beta, pol e lyase activity short patch - removes abasic nt e fills in 1 nt gap (after bDG funct) long patch - cannot remove, needs APE1 to do that, then can add multiple nts, results in flap, FEN1 has to cleave it
62
BER: ligation
LIG3 (post short patch) or LIG1 (post long patch) seals nick
63
cleansing the nt pool
MTH1 prevents addition of oxidized ATP e GTP CMPK1 discriminates between oxidized e unmodified cytidine using cytidine deaminase allows incorporation of dUTP into DNA > cancer treatement
64
NER overview
recog: global genomic damage or transcription coupled, recog bulky adducts like intrastrand crosslinks oligonucleotide excision (XPG e XPF) DNA pol syn new strand DNA ligase seals nick
65
NER: global genomic v transcription coupled damage recog
global genomic - recog by XPC, detects small region of ssDNA that results form bulk lesions, flips out 2 nts from *undamaged* DNA strand, if bulky lesion doesn't make ssDNA, recog by DDB instead of XPC transcription coupled - RNA pol reaches damaged area, stalls, CSB (already bound to pol) recruits CSA e UVSSA, RNA pol backtracks to expose damaged bases, if RNA pol cannot backup transcription will terminate, outcome based off timing
66
NER: repair
TFIIH binds, helicase subunit XPB opens DNA, XPD verifies damage, RPA coats undamaged strand XPF cuts damaged strand 5' to lesion > PCNA is immediately loaded XPG cuts damaged strand 3' to lesion PCNA recruits DNA pol (delta, kappa, or epsilon) ligase 1 or 3 joins the nick
67
NER: preincision complexes
PIC1 least stable, then PIC2, then PIC3 is most stable requires ATP for funct [[[XPA, RPA, XPC, TFIIH] + XPG] + XPF]
68
NER: chromatin
GG occurs in in close chromatin, TC in open DDB (GG) recruits acetyltransferases e chromatin remodelers CSB (TC) can modify e recruit histone modifiers, but already open bc transcription is happening
69
how does BER e NER crosstalk
dep on context when damage is detected: active or inactive chromatin? before or after DNA rep? SSB can become DSB
70
HR overview
recog: MRN binds DSBs multiple helicases unwind DNA MRN exonuclease creates ss tail > ssDNA is coated w RPA repair: RAD51/BRCA2 stim strand invasion, strands cross over and form D loop > form homology w daughter or sister chromatid > open 3' end is extended by DNA pol using homology as template ligase seals strands > forms Holliday junctions > need branch migration e Holliday junct resolution
71
HR: damage recog
recog e bound by MRN complex recruits ATM (PIKK kinase) > autophos e phos histones e other > chromatin remodeling e exonuclease resection DSBs are more likely between histones, makes them easier to recog than BER or NER
72
HR: finding homology
nuclease creates ss overhang > coat w RPA > BRCA2 replaces RPA w RAD51 > BRCA1-BARD1 stim invasion of dsDNA by RAD51, formation of D loop, e search for homology
73
how do PARP inhibitors treat cancer
SSB > use PARPi > SSB becomes DSB > normal cells will repair the DSB, BRCA def cells cannot repair the DSB > die
74
HR: Holliday Junctions
result from the crossing over e subsequent repair during HR use RuvAB > binds Holliday Junction > RuvC nicks > helicase e ATP stim branch migration > RuvC reseals resolved DNA can result in crossover recombinants MMR can repair mismatch if needed
75
DDR sensors
PARP for strand breaks, build up of proteins / stalling results in activation of ATM e ATR
76
role of ATM in DDR
ATM (PIKK kinase) recruited to DSB by MRN ATM activates CHK2 kinase e stabilizes p53 > cell cycle arrest, senescence, apoptosis phos H2AX > gammaH2AX marks DNA damage, silences transcription e recruit other proteins
77
gammaH2AX in DDR
marker of DSB e repair foci phos by ATM e ATR phos histone variant of H2A higher conc in coding e reg regions
78
MDC1 in DDR
gammaH2AX > MDC1 > MRN - amp signal MDC1 - blocks HR e allows NHEJ gammaH2AX reader, co-localizes w it recruits proteins to DDR foci
79
role of ATR in DDR
med DDR during DNA rep ATR/ATRIP binds RPA, phos by TopB1 e ETAA1 > activates ATR/ATRIP > phos CHK1 > stop cell cycle Rad17 - alt clamp loader, loads the 911 clamp at 5' recessed end (only present in damage) 911 clamp interacts w ATR / ATRIP *stop cell cycle, blocks chromatin remodelers, stop rep fork* need both ATR e TOPB1 for activation, loss of either is lethal
80
role of ATR in origin firing
resp to rep stress prevents firing when DNA is damaged S phase e early G2 pauses cell cycle: blocks global initiation at distant origins, promotes activation in areas near damage (not known why)
81
shelterin in DDR
prevents DDR from triggering on ends of DNA
82
role of PARPs in DDR
early DNA damage sensor, mostly PARP1, PARP2 does minor repair poly ribosylates self e proteins > large branching structures, can recruit other proteins poly ribosylation is neg charge, helps loosen association w DNA, might also help form condensates
83
role of PARP1 in excision repair
detects SSB, recruit XRCC1 (scaffold), BER ligase, e pol beta in GG-NER (not TC), recruited by DDB that recog bulky lesion PARP1 imp as DNA damage detector and recruitment of repair factors, PARP2 only recog SSB
84
synthetic lethality
use of PARPi > SSBs are not repaired, become DSBs BRCA mut cells (like in breast cancer) cannot do HR > cell death wt cells have BRCA, do not die
85
ATM v ATR
ATM responds to DSBs (and other damage) primarily activates G1/S & G2/M checkpoints but also intra-S ATR responds to replication stress primarily activates intra-S checkpoint but also G2/M activation
86
cell cycle goal
the timely e accurate duplication e segregation of genomic DNA
87
CDK activity during cell cycle overview
pre-rep: CDK inc high during S phase inc again during mitotic entry (decision window) drops during mitotic exit (end of metaphase)
88
APC/C activity during cell cycle overview
pre-rep: high drops during decision window to enter rep low during S phase inc during mitotic exit (end of metaphase)
89
G1/S transition checkpt
should cell enter cell cycle? cyclin D inc > monophos RB, p107, e p130 E2F is released, makes more cyclin E cyclin E > polyphos RB, p107, e p130 > pos feedback loop ensures progression of cell cycle to S phase commitment to enter S dep on cyclin A/CDK2
90
role of cyclin A in cell cycle
commits cell to enter S phase cyclinA-CDK1/2 is req to load Cdc45 to make CMG complex
91
G2/M transition checkpt
The decision to enter mitosis is driven by the accumulation of cyclin A/B-CKD1 activity cyclin A is stable, B inc Cdc25 activates cyclin B, WEE1 deactivates it make sure DNA is good, prevent accumulation / propagation of genetic errors
92
DNA quality control in cell cycle
Chk1 inhibits Cdc25 damage results in Chk2 med cdc25 phos e degradation
93
mitotic entry checkpt
wave of CDK1 mediated mitotic phos causes dramatic changes in cellular architecture activation of APC/C rounding, centrosome separation, condensation of chr, nucleolar disassembly e permeabilization of nuc env
94
spindle assembly checkpoint
checkpt before commit to mitotic exit kinetochore attaches centromere to spindle fibers funct as chk pt before sep sister chromatids halts progress until all req met SAC on by default, inhibits APC/C ensures that APC can be shut down again later
95
'wait anaphase signal'
from unattached kinetochores inhibits APC/C CDC20 goes to mitotic checkpt complex (MCC); directly binds APC e inhibits its activity / funct
96
activation of APC/C
switch from APC/C inhibition to activation is med by UbcH10 by catalyzing dissociation of chkpt components from APC cdc20 becomes ub > dissociation of MCC Need cyclin B / CDK1
97
cell cycle cyclins: how specialized are they? how redundant
largely based on a quantitative increase in CDK activity through the cell cycle, combined with minor qualitative differences in the catalytic specialization of S-CDKs and M-CDKs the level of CDKs is most imp
98
cancer's affect on cell cycle checkpts
Genes involved in rep stress chkpt are rarely mut in cancer cells, as many cancers dep on chkpt funct to tolerate high levels of rep stress Cancer cells also rely on a funct mitotic chkpt to prevent catastrophic genome instability e death
99
outcomes of fork stalling
pathway determined by PCNA modification > stalling e RPA buildup both cause PCNA to be ub translesion syn - from mono-ub PCNA template switching - from poly-ub PCNA fork reversal - from poly-ub PCNA
100
TLS overview
allows cells to bypass e rep past DNA damage need special TLS DNA pol, which have lower fidelity e efficiency than reg rep pol can accommodate non-watson-crick bps
101
characteristics of TLS polymerases
low fidelity (rel to rep pol) active site is larger
102
TLS pol eta
Incorporates opposite of thymine cyclobutane dimers and 8-oxoG, error free
103
TLS pol REV1
Incorporates opposite of abasic sites, minor groove and exocyclic G adducts. Always inserts C = error prone.
104
TLS pol zeta
Works after other TLS pols insert. Mismatch and paired lesion extender
105
TLS pol iota
Accommodates Hoogsteen conformations. Incorporates opposite minor groove purine adducts and exocyclic G adducts
106
TLS pol kappa
Works after other TLS pols insert. Nucleotide-lesion extender. Bypass minor groove and exocyclic purine adducts
107
Fork repriming
promotes restart of DNA rep after stalled rep can skip over lesions leaving gap to be repaired later PrimPol can initiate rep wo RNA primers on the leading strand pol alpha / primase can make primers for lagging strand template switching can be used to fill in the gaps later, copies undamaged strand
108
Fork reversal
prevents degradation e larger strand breakdown, slows down rep can protect against time dep mech if rep fork has stalled for too long BRCA2 recruits RAD51 RAD51 stabilizes filamentation, protects against collapse e degradation, protects against neucleolytic cleavage, ZRANB3 binds poly-ub PCNA e SMARCAL1 help unwind newly syn strands e anneal nascent e parental strands together
109
Fork restart
reg by PARP1, suppresses RECQ1 until damage is repaired only PARP1, not PARP2
110
Fork collapse e repair
stalling at SSB might create DSB
111
ICL repair by FA pathway
rep fork encounter interstrand crosslink, replisome removed, RAD51 protects fork, FA complex recruited, ub-FANC1 e ub-FANCD2 encircle DNA, incisions made by nucleases around ICL, cut out e unhook from DNA, pol zeta med TLS across lesion, HR repairs DSB

Adv Mol and Cell Bio (BCH 6415) (4 decks)

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