Processing of DNA double-strand break ends

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R-HSA-5693607
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Pathway
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Homo sapiens
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Homology directed repair (HDR) through homologous recombination (HRR) or single strand annealing (SSA) requires extensive resection of DNA double-strand break (DSB) ends (Thompson and Limoli 2003, Ciccia and Elledge 2010). The resection is performed in a two-step process, where the MRN complex (MRE11A:RAD50:NBN) and RBBP8 (CtIP) bound to BRCA1 initiate the resection. This step is regulated by the complex of CDK2 and CCNA (cyclin A), ensuring the initiation of HRR during S and G2 phases of the cell cycle, when sister chromatids are available. The initial resection is also regulated by ATM-mediated phosphorylation of RBBP8 and CHEK2-mediated phosphorylation of BRCA1 (Chen et al. 2008, Yun and Hiom 2009, Buis et al. 2012, Wang et al. 2013, Davies et al. 2015, Parameswaran et al. 2015). After the initial resection, DNA nucleases EXO1 and/or DNA2 perform long-range resection, which is facilitated by DNA helicases BLM or WRN, as well as BRIP1 (BACH1) (Chen et al. 2008, Nimonkar et al. 2011, Sturzenegger et al. 2014, Suhasini et al. 2011). The resulting long 3'-ssDNA overhangs are coated by the RPA heterotrimers (RPA1:RPA2:RPA3), which recruit ATR:ATRIP complexes to DNA DSBs and, in collaboration with RAD17:RFC and RAD9:HUS1:RAD1 complexes, and TOPBP1 and RHNO1, activate ATR signaling. Activated ATR phosphorylates RPA2 and activates CHEK1 (Cotta-Ramusino et al. 2011), both of which are necessary prerequisites for the subsequent steps in HRR and SSA.

Literature References
PubMed ID Title Journal Year
21240188 Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom's syndrome

Rawtani, NA, Hickson, ID, North, PS, Cantor, SB, Mosedale, G, Sommers, JA, Suhasini, AN, Wu, Y, Brosh, RM, Sharma, S

EMBO J. 2011
19357644 CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle

Yun, MH, Hiom, K

Nature 2009
21659603 A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling

Hurov, K, Elledge, SJ, Cotta-Ramusino, C, McDonald, ER, Sowa, ME, Harper, JW

Science 2011
22231403 Mre11 regulates CtIP-dependent double-strand break repair by interaction with CDK2

Stoneham, T, Buis, J, Spehalski, E, Ferguson, DO

Nat. Struct. Mol. Biol. 2012
25659039 Damage-induced BRCA1 phosphorylation by Chk2 contributes to the timing of end resection

Lu, Y, Chiang, HC, Baer, RJ, Parameswaran, B, Li, R, Coates, J, Lin, HK, Deng, CX, Hu, Y, Paull, TT

Cell Cycle 2015
21325134 BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair

Modrich, P, Polaczek, P, Wyman, C, Nimonkar, AV, Campbell, JL, Genschel, J, Kinoshita, E, Kowalczykowski, SC

Genes Dev. 2011
20965415 The DNA damage response: making it safe to play with knives

Elledge, SJ, Ciccia, A

Mol. Cell 2010
25558984 CtIP tetramer assembly is required for DNA-end resection and repair

Morton, CR, Forment, JV, Pellegrini, L, Jackson, SP, Coates, J, Galanty, Y, Belotserkovskaya, R, Demir, M, Sun, M, Davies, OR, Rzechorzek, NJ

Nat. Struct. Mol. Biol. 2015
23468639 The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair

Wang, H, Yates, JR, Chen, DJ, Shi, LZ, Han, X, Wong, CC, Wu, X, Zhu, Q, Berns, MW, Shao, Z, Truong, LN, Chen, L, Hwang, PY

PLoS Genet. 2013
25122754 DNA2 cooperates with the WRN and BLM RecQ helicases to mediate long-range DNA end resection in human cells

Pinto, C, Burdova, K, Sturzenegger, A, Janscak, P, Kanagaraj, R, Cejka, P, Levikova, M

J. Biol. Chem. 2014
18171670 Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair

Wu, X, Lee, AY, Nievera, CJ, Chen, L

J. Biol. Chem. 2008
  Eukaryotic DNA Damage Surveillance and Repair

Caldecott, KW

  2004
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