Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage.
NIPBL is required to load the cohesin complex on to DNA. While the canonical role of cohesin is to couple replicated sister chromatids together until the onset of mitosis, it also promotes tolerance to DNA damage. Here, we show that NIPBL is recruited to DNA damage throughout the cell cycle via independent mechanisms, influenced by type of damage. First, the heterochromatin protein HP1γ (also known as CBX3) recruits NIPBL to DNA double-strand breaks (DSBs) through the corresponding HP1-binding motif within the N-terminus. By contrast, the C-terminal HEAT repeat domain is unable to recruit NIPBL to DSBs but independently targets NIPBL to laser microirradiation-induced DNA damage. Each mechanism is dependent on the RNF8 and RNF168 ubiquitylation pathway, while the recruitment of the HEAT repeat domain requires further ATM or ATR activity. Thus, NIPBL has evolved a sophisticated response to damaged DNA that is influenced by the form of damage, suggesting a highly dynamic role for NIPBL in maintaining genomic stability.
Karolinska Institutet, Department of Cell and Molecular Biology, Stockholm 171 77, Sweden.
Christopher
C
Bot
Karolinska Institutet, Department of Cell and Molecular Biology, Stockholm 171 77, Sweden.
Annika
A
Pfeiffer
Karolinska Institutet, Department of Cell and Molecular Biology, Stockholm 171 77, Sweden.
Fosco
F
Giordano
Karolinska Institutet, Department of Cell and Molecular Biology, Stockholm 171 77, Sweden.
Dharani E
0000-0002-1692-0704
DE
Manjeera
Karolinska Institutet, Department of Cell and Molecular Biology, Stockholm 171 77, Sweden.
Nico P
NP
Dantuma
Karolinska Institutet, Department of Cell and Molecular Biology, Stockholm 171 77, Sweden lena.strom@ki.se.
Lena
L
Ström
D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004268:DNA-Binding Proteins; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008954:Models, Biological; D000072417:Protein Domains; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000097722:Cohesins
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D049452:Green Fluorescent Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000097722:Cohesins; C515655:MAU2 protein, human; C487465:NIPBL protein, human; C576597:ATR protein, human
Cohesin; DNA damage; DNA damage recruitment; Genome stability; Laser microirradiation; NIPBL