EXO1 or DNA2 in complex with BLM or WRN binds initially resected DNA DSBs along with BRIP1 recruitment

Stable Identifier
R-HSA-5685985
Type
Reaction [binding]
Species
Homo sapiens
Compartment
nucleoplasm
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EXO1 or DNA2 in complex with BLM or WRN binds initially resected DNA DSBs along with BRIP1 recruitment
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After the initial resection of DNA double strand breaks (DSBs) by MRE11A and RBBP8 (CtIP), which creates short 3' ssDNA overhangs, a DNA exonuclease EXO1 or a DNA endonuclease DNA2 is recruited to perform long-range resection of DNA DSBs. The redundant function of EXO1 and DNA2 in resection of DNA DSBs is conserved in yeast (Zhu et al. 2008). BLM, the Bloom syndrome helicase, acts as an activator of DNA2 catalytic activity (Nimonkar et al. 2011) and increases affinity of EXO1 for DNA ends (Nimonkar et al. 2008). BLM directly interacts with the MRN complex, which can assist recruitment of either DNA2 or EXO1 to DNA DSBs (Nimonkar et al. 2011). EXO1 can also be recruited to DNA DSBs through its interaction with RBBP8 (CtIP) (Eid et al. 2010, Nimonkar et al. 2011). Another DNA helicase, WRN (Werner syndrome helicase) can function redundantly with BLM to facilitate/activate EXO1- or DNA2-mediated long range resection of DNA DSBs (Sturzenegger et al. 2014).

A DNA helicase BRIP1 (also known as BACH1 or FANCJ) is recruited to DNA DSBs through its interaction with BRCA1 (Cantor et al. 2001) and BLM (Suhasini et al. 2011, Suhasini and Brosh 2012). BRIP1 promotes DNA end processing events that stimulate recruitment of the RPA complex and RAD51 (Xie et al. 2012). The interaction with BRCA1 requires BRIP1 to be phosphorylated on serine residue S990 in a cell cycle-dependent manner (Yu et al. 2003). BRIP1 also has to be acetylated on lysine residue K1249 to be functional (Xie et al. 2012).

Literature References
PubMed ID Title Journal Year
18971343 Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair

Nimonkar, AV, Ozsoy, AZ, Genschel, J, Modrich, P, Kowalczykowski, SC

Proc. Natl. Acad. Sci. U.S.A. 2008
16153896 BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ

Litman, R, Peng, M, Jin, Z, Zhang, F, Zhang, J, Powell, S, Andreassen, PR, Cantor, SB

Cancer Cell 2005
18805091 Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends

Zhu, Z, Chung, WH, Shim, EY, Lee, SE, Ira, G

Cell 2008
14576433 The BRCT domain is a phospho-protein binding domain

Yu, X, Chini, CC, He, M, Mer, G, Chen, J

Science 2003
11301010 BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function

Cantor, SB, Bell, DW, Ganesan, S, Kass, EM, Drapkin, R, Grossman, S, Wahrer, DC, Sgroi, DC, Lane, WS, Haber, DA, Livingston, DM

Cell 2001
22024395 Fanconi anemia and Bloom's syndrome crosstalk through FANCJ-BLM helicase interaction

Suhasini, AN, Brosh, RM

Trends Genet. 2012
21325134 BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair

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

Genes Dev. 2011
21052091 DNA end resection by CtIP and exonuclease 1 prevents genomic instability

Eid, W, Steger, M, El-Shemerly, M, Ferretti, LP, Peña-Diaz, J, König, C, Valtorta, E, Sartori, AA, Ferrari, S

EMBO Rep. 2010
22792074 FANCJ/BACH1 acetylation at lysine 1249 regulates the DNA damage response

Xie, J, Peng, M, Guillemette, S, Quan, S, Maniatis, S, Wu, Y, Venkatesh, A, Shaffer, SA, Brosh, RM, Cantor, SB

PLoS Genet. 2012
25122754 DNA2 cooperates with the WRN and BLM RecQ helicases to mediate long-range DNA end resection in human cells

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

J. Biol. Chem. 2014
21240188 Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom's syndrome

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

EMBO J. 2011
Participants
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Orthologous Events
EXO1 or DNA2 in complex with BLM or WRN binds initially resected DNA DSBs along with BRIP1 recruitment (Caenorhabditis elegans)
EXO1 or DNA2 in complex with BLM or WRN binds initially resected DNA DSBs along with BRIP1 recruitment (Canis familiaris)
EXO1 or DNA2 in complex with BLM or WRN binds initially resected DNA DSBs along with BRIP1 recruitment (Danio rerio)
EXO1 or DNA2 in complex with BLM or WRN binds initially resected DNA DSBs along with BRIP1 recruitment (Mus musculus)
EXO1 or DNA2 in complex with BLM or WRN binds initially resected DNA DSBs along with BRIP1 recruitment (Rattus norvegicus)
EXO1 or DNA2 in complex with BLM or WRN binds initially resected DNA DSBs along with BRIP1 recruitment (Sus scrofa)
EXO1 or DNA2 in complex with BLM or WRN binds initially resected DNA DSBs along with BRIP1 recruitment (Xenopus tropicalis)
Authored
Orlic-Milacic, M  (2015-05-12)
Reviewed
Borowiec, JA  (2015-06-12)
Created
Orlic-Milacic, M  (2015-03-31)
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