TY - JOUR
T1 - DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation
AU - Kwon, Youngho
AU - Rösner, Heike
AU - Zhao, Weixing
AU - Selemenakis, Platon
AU - He, Zhuoling
AU - Kawale, Ajinkya S.
AU - Katz, Jeffrey N.
AU - Rogers, Cody M.
AU - Neal, Francisco E.
AU - Badamchi Shabestari, Aida
AU - Petrosius, Valdemaras
AU - Singh, Akhilesh K.
AU - Joel, Marina Z.
AU - Lu, Lucy
AU - Holloway, Stephen P.
AU - Burma, Sandeep
AU - Mukherjee, Bipasha
AU - Hromas, Robert
AU - Mazin, Alexander
AU - Wiese, Claudia
AU - Sørensen, Claus S.
AU - Sung, Patrick
N1 - Funding Information:
This study was supported by research grants from the US National Institutes of Health (RO1 CA168635, RO1 ES007061, PO1 CA92584, R35 CA241801 (P.S.); R50 CA265315 (Y.K.); R01 GM141091 and R01 CA268641 (W.Z.); R01 GM136717, R01 CA23728, R01 CA188347 (A.M.); R56 ES021454 (C.W.); R01CA246807 (S.B.), Danish Cancer Society (R167-A10921-B224) (C.S.), Cancer Prevention and Research Institute of Texas (CPRIT) (RP220269) (R.H.) and RP210102 (W.Z.), Congressionally Directed Medical Research Programs (BC191160) (A.M.), and a Gray Foundation Team Science Grant under the Basser Initiative (P.S.), ACS Postdoctoral Fellowship (PF-22-034-01-DMC) (C.M.R.), CPRIT Postdoctoral Fellowship (RP170345) (A.S.K.), and NIH predoctoral fellowship awards (F30CA260908, T32CA148724) (F.E.N.). P.S. is the holder of the Robert A. Welch Distinguished Chair in Chemistry (AQ-0012) and recipient of a Recruitment of Established Investigators Award from CPRIT (RR180029). A.M. is the holder of the Joe R. and Teresa Lozano Long Chair in Cancer and recipient of a Recruitment of Established Investigators Award from CPRIT (RR210023). S.B. is the holder of the Mays Family Foundation Distinguished Chair in Oncology.
Funding Information:
This study was supported by research grants from the US National Institutes of Health (RO1 CA168635, RO1 ES007061, PO1 CA92584, R35 CA241801 (P.S.); R50 CA265315 (Y.K.); R01 GM141091 and R01 CA268641 (W.Z.); R01 GM136717, R01 CA23728, R01 CA188347 (A.M.); R56 ES021454 (C.W.); R01CA246807 (S.B.), Danish Cancer Society (R167-A10921-B224) (C.S.), Cancer Prevention and Research Institute of Texas (CPRIT) (RP220269) (R.H.) and RP210102 (W.Z.), Congressionally Directed Medical Research Programs (BC191160) (A.M.), and a Gray Foundation Team Science Grant under the Basser Initiative (P.S.), ACS Postdoctoral Fellowship (PF-22-034-01-DMC) (C.M.R.), CPRIT Postdoctoral Fellowship (RP170345) (A.S.K.), and NIH predoctoral fellowship awards (F30CA260908, T32CA148724) (F.E.N.). P.S. is the holder of the Robert A. Welch Distinguished Chair in Chemistry (AQ-0012) and recipient of a Recruitment of Established Investigators Award from CPRIT (RR180029). A.M. is the holder of the Joe R. and Teresa Lozano Long Chair in Cancer and recipient of a Recruitment of Established Investigators Award from CPRIT (RR210023). S.B. is the holder of the Mays Family Foundation Distinguished Chair in Oncology.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - The tumor suppressor BRCA2 participates in DNA double-strand break repair by RAD51-dependent homologous recombination and protects stressed DNA replication forks from nucleolytic attack. We demonstrate that the C-terminal Recombinase Binding (CTRB) region of BRCA2, encoded by gene exon 27, harbors a DNA binding activity. CTRB alone stimulates the DNA strand exchange activity of RAD51 and permits the utilization of RPA-coated ssDNA by RAD51 for strand exchange. Moreover, CTRB functionally synergizes with the Oligonucleotide Binding fold containing DNA binding domain and BRC4 repeat of BRCA2 in RPA-RAD51 exchange on ssDNA. Importantly, we show that the DNA binding and RAD51 interaction attributes of the CTRB are crucial for homologous recombination and protection of replication forks against MRE11-mediated attrition. Our findings shed light on the role of the CTRB region in genome repair, reveal remarkable functional plasticity of BRCA2, and help explain why deletion of Brca2 exon 27 impacts upon embryonic lethality.
AB - The tumor suppressor BRCA2 participates in DNA double-strand break repair by RAD51-dependent homologous recombination and protects stressed DNA replication forks from nucleolytic attack. We demonstrate that the C-terminal Recombinase Binding (CTRB) region of BRCA2, encoded by gene exon 27, harbors a DNA binding activity. CTRB alone stimulates the DNA strand exchange activity of RAD51 and permits the utilization of RPA-coated ssDNA by RAD51 for strand exchange. Moreover, CTRB functionally synergizes with the Oligonucleotide Binding fold containing DNA binding domain and BRC4 repeat of BRCA2 in RPA-RAD51 exchange on ssDNA. Importantly, we show that the DNA binding and RAD51 interaction attributes of the CTRB are crucial for homologous recombination and protection of replication forks against MRE11-mediated attrition. Our findings shed light on the role of the CTRB region in genome repair, reveal remarkable functional plasticity of BRCA2, and help explain why deletion of Brca2 exon 27 impacts upon embryonic lethality.
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UR - http://www.scopus.com/inward/citedby.url?scp=85146898771&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-36211-x
DO - 10.1038/s41467-023-36211-x
M3 - Article
C2 - 36702902
AN - SCOPUS:85146898771
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 432
ER -