2. Academic Validation
  3. Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability

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

  • Mol Cell. 2016 Feb 18;61(4):535-546. doi: 10.1016/j.molcel.2015.12.026.
Kelly S Trego 1,  Torsten Groesser 1,  Albert R Davalos 2,  Ann C Parplys 1,  Weixing Zhao 3,  Michael R Nelson 1,  Ayesu Hlaing 1,  Brian Shih 1,  Björn Rydberg 1,  Janice M Pluth 1,  Miaw-Sheue Tsai 1,  Jan H J Hoeijmakers 4,  Patrick Sung 3,  Claudia Wiese 1,  Judith Campisi 5,  Priscilla K Cooper 6
Affiliations

Affiliations

  • 1 Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
  • 2 The Buck Institute for Research on Aging, Novato, CA 94945, USA.
  • 3 Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 4 Department of Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
  • 5 Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; The Buck Institute for Research on Aging, Novato, CA 94945, USA.
  • 6 Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: [email protected].
PMID: 26833090 DOI: 10.1016/j.molcel.2015.12.026
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.

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