TY - JOUR
T1 - NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability
AU - Parplys, Ann C.
AU - Zhao, Weixing
AU - Sharma, Neelam
AU - Groesser, Torsten
AU - Liang, Fengshan
AU - Maranon, David G.
AU - Leung, Stanley G.
AU - Grundt, Kirsten
AU - Dray, Eloïse
AU - Idate, Rupa
AU - Østvold, Anne Carine
AU - Schild, David
AU - Sung, Patrick
AU - Wiese, Claudia
N1 - Publisher Copyright:
© 2015 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2015/8/17
Y1 - 2015/8/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84950111507&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84950111507&partnerID=8YFLogxK
U2 - 10.1093/nar/gkv859
DO - 10.1093/nar/gkv859
M3 - Article
C2 - 26323318
AN - SCOPUS:84950111507
SN - 0305-1048
VL - 43
SP - 9817
EP - 9834
JO - Nucleic acids research
JF - Nucleic acids research
IS - 20
ER -