2. Academic Validation
  3. NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability

NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability

  • Nucleic Acids Res. 2015 Nov 16;43(20):9817-34. doi: 10.1093/nar/gkv859.
Ann C Parplys 1,  Weixing Zhao 2,  Neelam Sharma 3,  Torsten Groesser 1,  Fengshan Liang 2,  David G Maranon 3,  Stanley G Leung 1,  Kirsten Grundt 4,  Eloïse Dray 2,  Rupa Idate 3,  Anne Carine Østvold 4,  David Schild 1,  Patrick Sung 2,  Claudia Wiese 5
Affiliations

Affiliations

  • 1 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
  • 2 Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 3 Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
  • 4 Department of Molecular Medicine, Institute of Basic Medical Science, University of Oslo, 0317 Oslo, Norway.
  • 5 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA [email protected].
PMID: 26323318 DOI: 10.1093/nar/gkv859
Abstract

NUCKS1 (nuclear Casein Kinase and cyclin-dependent kinase substrate 1) is a 27 kD chromosomal, vertebrate-specific protein, for which limited functional data exist. Here, we demonstrate that NUCKS1 shares extensive sequence homology with RAD51AP1 (RAD51 associated protein 1), suggesting that these two proteins are paralogs. Similar to the phenotypic effects of RAD51AP1 knockdown, we find that depletion of NUCKS1 in human cells impairs DNA repair by homologous recombination (HR) and chromosome stability. Depletion of NUCKS1 also results in greatly increased cellular sensitivity to mitomycin C (MMC), and in increased levels of spontaneous and MMC-induced chromatid breaks. NUCKS1 is critical to maintaining wild type HR capacity, and, as observed for a number of proteins involved in the HR pathway, functional loss of NUCKS1 leads to a slow down in DNA replication fork progression with a concomitant increase in the utilization of new replication origins. Interestingly, recombinant NUCKS1 shares the same DNA binding preference as RAD51AP1, but binds to DNA with reduced affinity when compared to RAD51AP1. Our results show that NUCKS1 is a chromatin-associated protein with a role in the DNA damage response and in HR, a DNA repair pathway critical for tumor suppression.

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