Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability
Abstract
XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. In this paper, we identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. Finally, these unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging.
- Authors:
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Inst. of Health (NIH) (United States)
- OSTI Identifier:
- 1344183
- Alternate Identifier(s):
- OSTI ID: 1379099
- Grant/Contract Number:
- AC02-05CH11231; R01 ES019935; P01 CA092584; R21 CA187765; P01 AG017242; R01 ES015252; R01 ES021454
- Resource Type:
- Published Article
- Journal Name:
- Molecular Cell
- Additional Journal Information:
- Journal Name: Molecular Cell Journal Volume: 61 Journal Issue: 4; Journal ID: ISSN 1097-2765
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Trego, Kelly S., Groesser, Torsten, Davalos, Albert R., Parplys, Ann C., Zhao, Weixing, Nelson, Michael R., Hlaing, Ayesu, Shih, Brian, Rydberg, Björn, Pluth, Janice M., Tsai, Miaw-Sheue, Hoeijmakers, Jan H. J., Sung, Patrick, Wiese, Claudia, Campisi, Judith, and Cooper, Priscilla K. Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability. United States: N. p., 2016.
Web. doi:10.1016/j.molcel.2015.12.026.
Trego, Kelly S., Groesser, Torsten, Davalos, Albert R., Parplys, Ann C., Zhao, Weixing, Nelson, Michael R., Hlaing, Ayesu, Shih, Brian, Rydberg, Björn, Pluth, Janice M., Tsai, Miaw-Sheue, Hoeijmakers, Jan H. J., Sung, Patrick, Wiese, Claudia, Campisi, Judith, & Cooper, Priscilla K. Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability. United States. https://doi.org/10.1016/j.molcel.2015.12.026
Trego, Kelly S., Groesser, Torsten, Davalos, Albert R., Parplys, Ann C., Zhao, Weixing, Nelson, Michael R., Hlaing, Ayesu, Shih, Brian, Rydberg, Björn, Pluth, Janice M., Tsai, Miaw-Sheue, Hoeijmakers, Jan H. J., Sung, Patrick, Wiese, Claudia, Campisi, Judith, and Cooper, Priscilla K. Mon .
"Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability". United States. https://doi.org/10.1016/j.molcel.2015.12.026.
@article{osti_1344183,
title = {Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability},
author = {Trego, Kelly S. and Groesser, Torsten and Davalos, Albert R. and Parplys, Ann C. and Zhao, Weixing and Nelson, Michael R. and Hlaing, Ayesu and Shih, Brian and Rydberg, Björn and Pluth, Janice M. and Tsai, Miaw-Sheue and Hoeijmakers, Jan H. J. and Sung, Patrick and Wiese, Claudia and Campisi, Judith and Cooper, Priscilla K.},
abstractNote = {XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. In this paper, we identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. Finally, these unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging.},
doi = {10.1016/j.molcel.2015.12.026},
journal = {Molecular Cell},
number = 4,
volume = 61,
place = {United States},
year = {Mon Feb 01 00:00:00 EST 2016},
month = {Mon Feb 01 00:00:00 EST 2016}
}
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https://doi.org/10.1016/j.molcel.2015.12.026
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Works referencing / citing this record:
Control of structure-specific endonucleases to maintain genome stability
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