Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability

Kelly S. Trego, Torsten Groesser, Albert R. Davalos, Ann C. Parplys, Weixing Zhao, Michael R. Nelson, Ayesu Hlaing, Brian Shih, Björn Rydberg, Janice M. Pluth, Miaw Sheue Tsai, Jan H.J. Hoeijmakers, Patrick Sung, Claudia Wiese, Judith Campisi, Priscilla K. Cooper

Research output: Contribution to journalArticle

18 Scopus citations

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. 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. 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. It is unclear how the loss of XPG protein causes the neurodevelopmental disorder Cockayne syndrome with death in early childhood. Trego et al. show that XPG partners with BRCA1 and BRCA2 to maintain genomic stability through homologous recombination, and its loss causes DNA breaks, chromosome aberrations, and replication fork stalling.

Original languageEnglish (US)
Pages (from-to)535-546
Number of pages12
JournalMolecular Cell
Volume61
Issue number4
DOIs
StatePublished - Feb 18 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Trego, K. S., Groesser, T., Davalos, A. R., Parplys, A. C., Zhao, W., Nelson, M. R., Hlaing, A., Shih, B., Rydberg, B., Pluth, J. M., Tsai, M. S., Hoeijmakers, J. H. J., Sung, P., Wiese, C., Campisi, J., & Cooper, P. K. (2016). Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability. Molecular Cell, 61(4), 535-546. https://doi.org/10.1016/j.molcel.2015.12.026