Widespread BRCA1/2-independent homologous recombination defects are caused by alterations in RNA-binding proteins

Daniel J. McGrail; Yang Li; Roger S. Smith; Bin Feng; Hui Dai; Limei Hu; Briana Dennehey; Sharad Awasthi; Marc L. Mendillo; Anil K. Sood; Gordon B. Mills; Shiaw Yih Lin; S. Stephen Yi; Nidhi Sahni

doi:10.1016/j.xcrm.2023.101255

Widespread BRCA1/2-independent homologous recombination defects are caused by alterations in RNA-binding proteins

Daniel J. McGrail^*, Yang Li, Roger S. Smith, Bin Feng, Hui Dai, Limei Hu, Briana Dennehey, Sharad Awasthi, Marc L. Mendillo, Anil K. Sood, Gordon B. Mills, Shiaw Yih Lin, S. Stephen Yi^*, Nidhi Sahni^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Defects in homologous recombination DNA repair (HRD) both predispose to cancer development and produce therapeutic vulnerabilities, making it critical to define the spectrum of genetic events that cause HRD. However, we found that mutations in BRCA1/2 and other canonical HR genes only identified 10%–20% of tumors that display genomic evidence of HRD. Using a networks-based approach, we discovered that over half of putative genes causing HRD originated outside of canonical DNA damage response genes, with a particular enrichment for RNA-binding protein (RBP)-encoding genes. These putative drivers of HRD were experimentally validated, cross-validated in an independent cohort, and enriched in cancer-associated genome-wide association study loci. Mechanistic studies indicate that some RBPs are recruited to sites of DNA damage to facilitate repair, whereas others control the expression of canonical HR genes. Overall, this study greatly expands the repertoire of known drivers of HRD, with implications for basic biology, genetic screening, and therapy stratification.

Original language	English (US)
Article number	101255
Journal	Cell Reports Medicine
Volume	4
Issue number	11
DOIs	https://doi.org/10.1016/j.xcrm.2023.101255
State	Published - Nov 21 2023

Funding

This work was supported by the National Cancer Institute's Office of Cancer Genomics Cancer Target Discovery and Development ( CTDˆ2 ) initiative. The work was also supported by Breast Cancer Alliance , Blanton-Davis Ovarian Cancer Research Program , Sidney Kimmel Foundation , Susan G. Komen Foundation , U.S. Department of Defense , and George and Barbara Bush Endowment . N.S. is a CPRIT Scholar in Cancer Research with funding from the Cancer Prevention and Research Institute of Texas ( CPRIT ) New Investigator Grant RR160021 . N.S. was supported by the Early Career Award funded by Ovarian Cancer Research Alliance grant #649968 , NIH grant R35GM137836 , Young Investigator grant from the Breast Cancer Alliance, and Blanton-Davis Ovarian Cancer Research Program . S.Y. was supported by NIGMS grant R35GM133658 and Komen Foundation grant CCR19609287 . D.J.M. was supported by Susan G. Komen PDF17483544 and NCI grant R00CA240689 . M.L.M. was supported by the Susan G. Komen Foundation ( CCR17488145 ), National Cancer Institute of the NIH ( R00CA175293 ), the Kimmel Scholar ( SKF-16-135 ), and Lynn Sage Scholar awards. A.K.S. was supported by SPORE in Ovarian Cancer ( CA216785 ), Ovarian Cancer Moon Shot , the American Cancer Society , and the Frank McGraw Memorial Chair in Cancer Research . Additional support was provided by a Department of Defense Era of Hope Scholar Award ( W81XWH-10-1-0558 ) and George and Barbara Bush Endowment for Innovative Cancer Research to S.-Y.L. and U01CA217842 to G.B.M. We appreciate MD Anderson Cancer Center core facilities funded by grant CA016672 : the Functional Genomics Core (shRNA and ORFeome Core) for reagents and technical assistance and the Characterized Cell Line Core for STR DNA fingerprinting and mycoplasma testing. The results here are in whole or part based upon data generated by the TCGA Research Network : http://cancergenome.nih.gov/ . This work was supported by the National Cancer Institute's Office of Cancer Genomics Cancer Target Discovery and Development (CTDˆ2) initiative. The work was also supported by Breast Cancer Alliance, Blanton-Davis Ovarian Cancer Research Program, Sidney Kimmel Foundation, Susan G. Komen Foundation, U.S. Department of Defense, and George and Barbara Bush Endowment. N.S. is a CPRIT Scholar in Cancer Research with funding from the Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator Grant RR160021. N.S. was supported by the Early Career Award funded by Ovarian Cancer Research Alliance grant #649968, NIH grant R35GM137836, Young Investigator grant from the Breast Cancer Alliance, and Blanton-Davis Ovarian Cancer Research Program. S.Y. was supported by NIGMS grant R35GM133658 and Komen Foundation grant CCR19609287. D.J.M. was supported by Susan G. Komen PDF17483544 and NCI grant R00CA240689. M.L.M. was supported by the Susan G. Komen Foundation (CCR17488145), National Cancer Institute of the NIH (R00CA175293), the Kimmel Scholar (SKF-16-135), and Lynn Sage Scholar awards. A.K.S. was supported by SPORE in Ovarian Cancer (CA216785), Ovarian Cancer Moon Shot, the American Cancer Society, and the Frank McGraw Memorial Chair in Cancer Research. Additional support was provided by a Department of Defense Era of Hope Scholar Award (W81XWH-10-1-0558) and George and Barbara Bush Endowment for Innovative Cancer Research to S.-Y.L. and U01CA217842 to G.B.M. We appreciate MD Anderson Cancer Center core facilities funded by grant CA016672: the Functional Genomics Core (shRNA and ORFeome Core) for reagents and technical assistance and the Characterized Cell Line Core for STR DNA fingerprinting and mycoplasma testing. The results here are in whole or part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. D.J.M. S.Y. and N.S. conceived the study; D.J.M. and N.S. wrote the manuscript with significant input from B.D. M.L.M, G.B.M. and S.Y. D.J.M. and B.F. performed computational analysis with input from G.B.M. S.Y. and N.S. D.J.M. conducted most of the experiments with help from N.S. R.S.S. Yang Li, and L.H. N.S. Yongsheng Li. and L.H. generated the allele libraries. N.S. R.S.S. and Yang Li performed siRNA treatment, library preparation, and RNA sequencing. S.-Y.L. S.Y. and N.S. provided intellectual input and supervision throughout the course of the study. All authors read and approved the final manuscript. G.B.M. consults with AstraZeneca, ImmunoMET, Ionis, Nuevolution, PDX bio, Signalchem, Symphogen, and Tarveda; has stock options with Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindle Top Ventures, and Tarveda; sponsored research from AstraZeneca, Immunomet, Pfizer, Nanostring, and Tesaro; has received travel support from Chrysallis Bio; and has licensed technology to Nanostring and Myriad Genetics. B.F. is an employee of AstraZeneca. A.K.S.: Consulting (Merck, Astra Zeneca, ImmunoGen, Iylon, GSK, Kiyatec); shareholder (BioPath); patent licensed (EGFL6 antibody).

Keywords

BRCA1
BRCA2
DNA damage
PARP inhibitors
RNA binding proteins
breast cancer
hereditary cancer
homologous recombination
network biology

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.xcrm.2023.101255

Cite this

McGrail, D. J., Li, Y., Smith, R. S., Feng, B., Dai, H., Hu, L., Dennehey, B., Awasthi, S., Mendillo, M. L., Sood, A. K., Mills, G. B., Lin, S. Y., Yi, S. S., & Sahni, N. (2023). Widespread BRCA1/2-independent homologous recombination defects are caused by alterations in RNA-binding proteins. Cell Reports Medicine, 4(11), Article 101255. https://doi.org/10.1016/j.xcrm.2023.101255

@article{e83b367c73304d288c0fc56f14bca760,

title = "Widespread BRCA1/2-independent homologous recombination defects are caused by alterations in RNA-binding proteins",

abstract = "Defects in homologous recombination DNA repair (HRD) both predispose to cancer development and produce therapeutic vulnerabilities, making it critical to define the spectrum of genetic events that cause HRD. However, we found that mutations in BRCA1/2 and other canonical HR genes only identified 10%–20% of tumors that display genomic evidence of HRD. Using a networks-based approach, we discovered that over half of putative genes causing HRD originated outside of canonical DNA damage response genes, with a particular enrichment for RNA-binding protein (RBP)-encoding genes. These putative drivers of HRD were experimentally validated, cross-validated in an independent cohort, and enriched in cancer-associated genome-wide association study loci. Mechanistic studies indicate that some RBPs are recruited to sites of DNA damage to facilitate repair, whereas others control the expression of canonical HR genes. Overall, this study greatly expands the repertoire of known drivers of HRD, with implications for basic biology, genetic screening, and therapy stratification.",

keywords = "BRCA1, BRCA2, DNA damage, PARP inhibitors, RNA binding proteins, breast cancer, hereditary cancer, homologous recombination, network biology",

author = "McGrail, {Daniel J.} and Yang Li and Smith, {Roger S.} and Bin Feng and Hui Dai and Limei Hu and Briana Dennehey and Sharad Awasthi and Mendillo, {Marc L.} and Sood, {Anil K.} and Mills, {Gordon B.} and Lin, {Shiaw Yih} and Yi, {S. Stephen} and Nidhi Sahni",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = nov,

day = "21",

doi = "10.1016/j.xcrm.2023.101255",

language = "English (US)",

volume = "4",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "11",

}

TY - JOUR

T1 - Widespread BRCA1/2-independent homologous recombination defects are caused by alterations in RNA-binding proteins

AU - McGrail, Daniel J.

AU - Li, Yang

AU - Smith, Roger S.

AU - Feng, Bin

AU - Dai, Hui

AU - Hu, Limei

AU - Dennehey, Briana

AU - Awasthi, Sharad

AU - Mendillo, Marc L.

AU - Sood, Anil K.

AU - Mills, Gordon B.

AU - Lin, Shiaw Yih

AU - Yi, S. Stephen

AU - Sahni, Nidhi

PY - 2023/11/21

Y1 - 2023/11/21

N2 - Defects in homologous recombination DNA repair (HRD) both predispose to cancer development and produce therapeutic vulnerabilities, making it critical to define the spectrum of genetic events that cause HRD. However, we found that mutations in BRCA1/2 and other canonical HR genes only identified 10%–20% of tumors that display genomic evidence of HRD. Using a networks-based approach, we discovered that over half of putative genes causing HRD originated outside of canonical DNA damage response genes, with a particular enrichment for RNA-binding protein (RBP)-encoding genes. These putative drivers of HRD were experimentally validated, cross-validated in an independent cohort, and enriched in cancer-associated genome-wide association study loci. Mechanistic studies indicate that some RBPs are recruited to sites of DNA damage to facilitate repair, whereas others control the expression of canonical HR genes. Overall, this study greatly expands the repertoire of known drivers of HRD, with implications for basic biology, genetic screening, and therapy stratification.

AB - Defects in homologous recombination DNA repair (HRD) both predispose to cancer development and produce therapeutic vulnerabilities, making it critical to define the spectrum of genetic events that cause HRD. However, we found that mutations in BRCA1/2 and other canonical HR genes only identified 10%–20% of tumors that display genomic evidence of HRD. Using a networks-based approach, we discovered that over half of putative genes causing HRD originated outside of canonical DNA damage response genes, with a particular enrichment for RNA-binding protein (RBP)-encoding genes. These putative drivers of HRD were experimentally validated, cross-validated in an independent cohort, and enriched in cancer-associated genome-wide association study loci. Mechanistic studies indicate that some RBPs are recruited to sites of DNA damage to facilitate repair, whereas others control the expression of canonical HR genes. Overall, this study greatly expands the repertoire of known drivers of HRD, with implications for basic biology, genetic screening, and therapy stratification.

KW - BRCA1

KW - BRCA2

KW - DNA damage

KW - PARP inhibitors

KW - RNA binding proteins

KW - breast cancer

KW - hereditary cancer

KW - homologous recombination

KW - network biology

UR - http://www.scopus.com/inward/record.url?scp=85177191073&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85177191073&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2023.101255

DO - 10.1016/j.xcrm.2023.101255

M3 - Article

C2 - 37909041

AN - SCOPUS:85177191073

SN - 2666-3791

VL - 4

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 11

M1 - 101255

ER -

Widespread BRCA1/2-independent homologous recombination defects are caused by alterations in RNA-binding proteins

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this