Long-range resection of DNA DSBs by EXO1 or DNA2

Stable Identifier
Reaction [transition]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

DNA nucleases EXO1 and DNA2 function redundantly in yeast (Zhu et al. 2008) and humans (Nimonkar et al. 2011) in long-range resection of DNA double-strand breaks (DSBs). Both DNA nucleases act after short 3' ssDNA overhangs are created by the initial resection of DNA DSBs mediated by MRE11A and RBBP8 (CtIP). The roles of BLM (Bloom syndrome helicase) and WRN (Werner syndrome helicase) in facilitation of EXO1- or DNA2-mediated resection of DNA DSBs are also redundant.

EXO1 possesses an intrinsic 5'->3' exonuclease activity. The ATPase activity of BLM DNA helicase is not required for EXO1 catalytic activity, but BLM increases the affinity of EXO1 for DNA ends (Nimonkar et al. 2008). WRN can also positively affect EXO1 exonuclease activity, although the mechanism is not clear (Sturzenegger et al. 2014).

The DNA endonuclease DNA2 has to form a complex with either BLM (Nimonkar et al. 2011) or WRN (Sturzenegger et al. 2014) in order to perform a 5'->3' directed resection of DNA DSBs. BLM forms an evolutionarily conserved complex with TOP3A, RMI1 and RMI2, known as the STR complex in yeast (Zhu et al. 2008) and the BTB or BTRR complex in humans. The entire BTRR complex participates in the activation of DNA2-mediated resection of DNA DSBs (Sturzenegger et al. 2014).

While ATR signaling may be detectable in the absence of long-range resection of DNA DSBs by EXO1 or DNA2 (Eid et al. 2010), EXO1 or DNA2 activity may be necessary to achieve biologically meaningful level of ATR activation (Gravel et al. 2008).

BRIP1 (BACH1, FANCJ) is a DNA helicase recruited to DNA DSBs by interaction with BRCA1 (Cantor et al. 2001) and BLM (Suhasini et al. 2011). BRIP1 is necessary for BRCA1-mediated homology-directed repair of DNA DSBs, and BRIP1 loss-of-function mutations are found in familial breast cancer (Cantor et al. 2001, Litman et al. 2005). The exact role of BRIP1 in DNA repair is not completely clear. BRIP1 is needed for the successful formation of RPA foci and, subsequently, RAD51 foci (Xie et al. 2012). The available evidence suggest that it cooperates with BLM in unwinding of DNA DSBs during resection (Suhasini et al. 2011, Sarkies et al. 2012), and may be especially important for unwinding of DNA that contains oxidative damage (Suhasini et al. 2009).

Literature References
PubMed ID Title Journal Year
16153896 BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ

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

Cancer Cell 2005
18971343 Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair

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

Proc. Natl. Acad. Sci. U.S.A. 2008
18805091 Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends

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

Cell 2008
18923075 DNA helicases Sgs1 and BLM promote DNA double-strand break resection

Magill, C, Gravel, S, Jackson, SP, Chapman, JR

Genes Dev. 2008
11301010 BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function

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

Cell 2001
19419957 FANCJ helicase uniquely senses oxidative base damage in either strand of duplex DNA and is stimulated by replication protein A to unwind the damaged DNA substrate in a strand-specific manner

Wold, MS, Camerini-Otero, RD, Voloshin, ON, Mason, AC, Sommers, JA, Suhasini, AN, Brosh, RM

J. Biol. Chem. 2009
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
22021381 FANCJ coordinates two pathways that maintain epigenetic stability at G-quadruplex DNA

Phillips, LG, Patel, KJ, Sarkies, P, Balasubramanian, S, Sale, JE, Murat, P

Nucleic Acids Res. 2012
21052091 DNA end resection by CtIP and exonuclease 1 prevents genomic instability

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

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

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

PLoS Genet. 2012
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
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
Catalyst Activity

deoxyribonuclease activity of 3' short overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 [nucleoplasm]

Orthologous Events
Cite Us!