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This content will become publicly available on August 31, 2015

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

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. Finally, 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.
 [1] ;  [2] ;  [3] ;  [1] ;  [2] ;  [3] ;  [1] ;  [4] ;  [2] ;  [3] ;  [4] ;  [1] ;  [2] ;  [5]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  2. Yale Univ. School of Medicine, New Haven, CT (United States)
  3. Colorado State Univ., Fort Collins, CO (United States)
  4. Univ. of Oslo (Norway)
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Colorado State Univ., Fort Collins, CO (United States)
Publication Date:
OSTI Identifier:
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Nucleic Acids Research
Additional Journal Information:
Journal Volume: 43; Journal Issue: 20; Journal ID: ISSN 0305-1048
Oxford University Press
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
Country of Publication:
United States