ANDREASSEN 4

Question 1

The DNA damage response (DDR) is critical for maintaining _________ and preventing human diseases such as _________.

Answer 1

genome stability, cancer

Question 2

The three major prongs of the DNA damage response are:

Answer 2

Cell cycle (checkpoint) arrest, DNA repair, Apoptosis

Question 3

List three key functions of the DDR

Answer 3

Detecting (sensing) DNA damage, Mediating subsequent signaling that arrests the cell cycle (as appropriate), Coordinately mediating signals that recruit and regulate DNA repair proteins.

Question 4

The term “DNA damage checkpoint” can refer to the arrest of a particular process such as _________, or to ________ in response to DNA damage.

Answer 4

a block to the firing of new origins, cell cycle arrest at a particular stage (like G2)

Question 5

Besides its role in maintaining genome stability, the DNA damage response is also important to _________ and _________.

Answer 5

cancer genetics, cancer therapy

Question 6

DNA-PK, ATM, and ATR are all _________ which are key transducers in DNA damage responses.

Answer 6

PI3K-related protein kinases

Question 7

ATM and ATR are sometimes called “__________” because deficiency for either of them perturbs certain checkpoints.

Answer 7

checkpoint kinases

Question 8

ATR and ATM have evolved to mediate and coordinate the response to _________ and _________, respectively.

Answer 8

replication stress, DSBs (double-strand breaks)

Question 9

Replication stress impedes _________ and can lead to _________.

Answer 9

DNA replication, fork collapse

Question 10

Fork collapse blocks _________ and can yield _________.

Answer 10

proliferation, DSBs

Question 11

ATR promotes DNA replication via the _________ checkpoint.

Answer 11

intra S

Question 12

Besides promoting DNA replication, ATR also recruits _________ necessary to restart stalled replication forks.

Answer 12

HR (homologous recombination) proteins

Question 13

DSBs must be repaired prior to _________ to ensure _________.

Answer 13

mitotic entry, chromosome integrity

Question 14

ATM recruits _________ necessary to repair DSBs.

Answer 14

HR proteins

Question 15

List three examples of replication stress-inducing agents

Answer 15

UV-C, HU (hydroxyurea), MMC (mitomycin C)

Question 16

List two examples of DSB-inducing agents

Answer 16

IR (ionizing radiation), Topo II inhibitors

Question 17

The sensor for DSBs is the _________ complex.

Answer 17

MRN (MRE11/Rad50/NBS1)

Question 18

List three sensors for replication stress

Answer 18

RPA, Rad17, H2AX

Question 19

ATM and ATR phosphorylate proteins with distinct roles in DNA damage responses, including:

Answer 19

Partner kinases – Chk1/Chk2, Sensors of DNA damage – NBS1, RPA, Rad9, Damage signaling – H2AX, BRCA1, Repair proteins – BLM, FANCI, Apoptosis/G1-S checkpoint – p53

Question 20

The partner checkpoint kinases for ATM and ATR are _________ and _________, respectively.

Answer 20

CHK2, CHK1

Question 21

The concept of cell cycle checkpoints was established by _________ and _________ in _________.

Answer 21

Hartwell, Weinert, 1989

Question 22

Cell cycle checkpoints act to ensure the _________ of cell cycle events.

Answer 22

order

Question 23

Potential consequences of a defect in checkpoints include _________, _________, and _________.

Answer 23

cell death, increased mutagenesis, infidelity in chromosome segregation

Question 24

DNA damage can cause checkpoint-dependent arrest of the cell cycle at the _________, within _________, and at _________ prior to mitotic entry.

Answer 24

G1-S transition, S phase (intra-S), G2

Question 25

Cell cycle arrest in response to DNA damage is mediated by _________ or _________ depending on the type of damage via control of _________.

Answer 25

ATM, ATR, cyclin-dependent kinases (CDKs)

Question 26

The G1 DNA damage checkpoint acts at the _________ restriction point.

Answer 26

Rb-dependent

Question 27

Seminal work on p53 and pRb was critical for understanding:

Answer 27

The role of tumor suppressors, Cell cycle control, Cell cycle checkpoints, DNA damage responses, Viral oncogenesis

Question 28

The MRN complex senses a _________ in chromatin and activates _________ ATM.

Answer 28

conformational change, dimeric

Question 29

Activated ATM phosphorylates many substrates including its partner, _________.

Answer 29

Chk2

Question 30

ATM-dependent phosphorylation of _________ (in the MRN complex) recruits/activates more ATM.

Answer 30

NBS1

Question 31

ATM-dependent phosphorylation of NBS1 is a _________ mechanism that amplifies ATM-dependent signaling.

Answer 31

feedback

Question 32

DNA damage response signaling events provide access of _________ to compacted chromatin.

Answer 32

DNA repair factors

Question 33

A critical ATM or ATR target in DSB and replication stress, respectively, is a variant histone ______ (______) present in nucleosomes.

Answer 33

H2A, H2AX

Question 34

MDC1 recruitment is the basis for subsequent _________ of H2A and H2AX, and further recruitment of DNA repair factors.

Answer 34

polyubiquitination

Question 35

RNF8 mediates ubiquitination of ______ (and/or ______).

Answer 35

H2A, H1

Question 36

Writers establish the _________ (acetylation, methylation, phosphorylation, or ubiquitination) on histones.

Answer 36

histone mark

Question 37

_________ is a "writer" of phosphorylation, while _________ is a polyubiquitin "writer."

Answer 37

ATM, RNF8

Question 38

Readers recognize and bind to histones modified with a particular _________ (acetylation, methylation, phosphorylation, or ubiquitination).

Answer 38

mark

Question 39

_________ is a “reader” of H2AX phosphorylation, and _________ is a "reader" of histone ubiquitination.

Answer 39

MDC1, RAP80

Question 40

K48-linked polyubiquitination targets proteins for _________.

Answer 40

proteasome-mediated degradation

Question 41

K63-linked polyubiquitination is involved in the recruitment of _________.

Answer 41

DDR proteins

Question 42

Signaling through gamma-H2AX and MDC1 coordinates HR: _________ (commitment) and _________ (initiation).

Answer 42

end resection, strand invasion

Question 43

53BP1 recognizes DNA damage-induced modifications of histones ______ and ______.

Answer 43

H2A, H4

Question 44

53BP1 promotes _________.

Answer 44

NHEJ (non-homologous end joining)

Question 45

PTIP and RIF1 block _________ (and HR), which permits binding of ______ proteins and ______ at the damage site to initiate NHEJ.

Answer 45

end resection, Ku, DNA-PK

Question 46

Potential consequences of a defect in checkpoints include cell death, increased _______, and infidelity in chromosome segregation.

Answer 46

mutagenesis

Question 47

Work with Xenopus extracts suggests that _______ at the fork continue to spool out ssDNA when damage is encountered.

Answer 47

helicases

Question 48

The 9-1-1 complex is a _______(shape) that slides until it encounters damage.

Answer 48

ring

Question 49

Among the chemical inhibitors for DNA-PK, ATM, or ATR, _______ inhibitors look most promising and may be effective as a monotherapy.

Answer 49

ATR

Question 50

P21 blocks CDK2 cyclin E activity at the _______ transition.

Answer 50

G1-S

Question 51

The release of _______ allows various cell cycle-related factors to be transcribed, particularly replication or S phase factors.

Answer 51

E2F

Question 52

Work that focused on p53 and pRb was critical in understanding the function of _______.

Answer 52

tumor suppressors

Question 53

ATM activates its sensor _______ in response to double-strand breaks.

Answer 53

MRN

Question 54

Ubiquitin conjugates have a diverse set of functions in cellular signaling, including _______, which is most important for transcriptional regulation.

Answer 54

monoubiquitination

Question 55

The MRN complex is the sensor for ATM, and one of its components, _______, is an enzyme involved in end resection.

Answer 55

MRE11

Question 56

___________ is a process that occurs at double-strand breaks and involves the removal of nucleotides from the 5' ends of the break to create 3' single-strand overhangs. These overhangs are necessary for homologous recombination to occur.

Answer 56

End resection

Question 57

True or False: The fact that the MRN complex is involved in both sensing damage and end resection suggests that these two processes are closely linked.

Answer 57

True

Question 58

ATR ___________ a variety of target proteins that are involved in the DNA damage response, including checkpoint activation, DNA repair, and apoptosis.

Answer 58

phosphorylates

Question 59

_______ is an example of an effector of apoptosis in the DNA damage response.

Answer 59

FANCI

Question 60

FANCI is a protein that is involved in the Fanconi anemia pathway, which is a DNA repair pathway that is important for repairing ________________.

Answer 60

interstrand crosslinks

Question 61

The decision between repairing a double-strand break by non-homologous end joining or homologous recombination may be influenced by the local _______ environment.

Answer 61

chromatin

Question 62

The 9-1-1 complex is made up of three proteins: Rad9, _____, and Hus1.

Answer 62

Rad1

Question 63

Fork collapse occurs when the replication fork, the structure that carries out DNA replication, encounters a _______ in the DNA template.

Answer 63

lesion

Question 64

When fork collapse occurs, DNA replication is ______, and this can lead to cell cycle arrest or cell death.

Answer 64

halted

Question 65

_______ is a protein that is involved in disassembling the displacement loop if it does not find proper homology during homologous recombination.

Answer 65

BLM

Question 66

During homologous recombination, a __________ loop (D-loop) is formed.

Answer 66

displacement

Question 67

BLM is thought to help disassemble the ________ if it does not find proper homology with the template. This helps to prevent the formation of non-homologous recombination products, which can lead to genomic instability.

Answer 67

D-loop

Question 68

Check1 phosphorylates CDC25A, leading to its _______, and thereby maintaining the inhibitory phosphorylation on CDK2.

Answer 68

degradation

Question 69

True or False: CDK2 is a CDK that is involved in promoting the transition from G1 to S phase.

Answer 69

True

Question 70

Ataxia telangiectasia and Nijmegen breakage syndrome are both rare genetic disorders that are characterized by a defect in the _______________.

Answer 70

DNA damage response (DDR)