SUMO in the mammalian response to DNA damage

2010 ◽  
Vol 38 (1) ◽  
pp. 92-97 ◽  
Author(s):  
Joanna R. Morris
Keyword(s):  
Dna Damage ◽  
Protein Interactions ◽  
Protein Function ◽  
Mammalian Cells ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Genotoxic Stress ◽  
Breast Cancer Susceptibility ◽  
Model Organisms ◽  
Breast Cancer Susceptibility Gene

Modification by SUMOs (small ubiquitin-related modifiers) is largely transient and considered to alter protein function through altered protein–protein interactions. These modifications are significant regulators of the response to DNA damage in eukaryotic model organisms and SUMOylation affects a large number of proteins in mammalian cells, including several proteins involved in the response to genomic lesions [Golebiowski, Matic, Tatham, Cole, Yin, Nakamura, Cox, Barton, Mann and Hay (2009) Sci. Signaling 2, ra24]. Furthermore, recent work [Morris, Boutell, Keppler, Densham, Weekes, Alamshah, Butler, Galanty, Pangon, Kiuchi, Ng and Solomon (2009) Nature 462, 886–890; Galanty, Belotserkovskaya, Coates, Polo, Miller and Jackson (2009) Nature 462, 935–939] has revealed the involvement of the SUMO cascade in the BRCA1 (breast-cancer susceptibility gene 1) pathway response after DNA damage. The present review examines roles described for the SUMO pathway in the way mammalian cells respond to genotoxic stress.

scholarly journals Functional Interaction of Monoubiquitinated FANCD2 and BRCA2/FANCD1 in Chromatin

2004 ◽  
Vol 24 (13) ◽  
pp. 5850-5862 ◽  
Author(s):  
XiaoZhe Wang ◽  
Paul R. Andreassen ◽  
Alan D. D'Andrea
Keyword(s):  
Dna Damage ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Breast Cancer Susceptibility ◽  
Functional Complementation ◽  
Breast Cancer Susceptibility Gene ◽  
Functional Interaction ◽  
C Terminus ◽  
Brca2 Protein ◽  
Carboxy Terminal

ABSTRACT Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome with at least 11 complementation groups (A, B, C, D1, D2, E, F, G, I, J, and L), and eight FA genes have been cloned. The FANCD1 gene is identical to the breast cancer susceptibility gene, BRCA2. The FA proteins cooperate in a common pathway, but the function of BRCA2/FANCD1 in this pathway remains unknown. Here we show that monoubiquitination of FANCD2, which is activated by DNA damage, is required for targeting of FANCD2 to chromatin, where it interacts with BRCA2. FANCD2-Ub then promotes BRCA2 loading into a chromatin complex. FANCD2−/− cells are deficient in the assembly of DNA damage-inducible BRCA2 foci and in chromatin loading of BRCA2. Functional complementation with the FANCD2 cDNA restores BRCA2 foci and its chromatin loading following DNA damage. BRCA2−/− cells expressing a carboxy-terminal truncated BRCA2 protein form IR-inducible BRCA2 and FANCD2 foci, but these foci fail to colocalize. Functional complementation of these cells with wild-type BRCA2 restores the interaction of BRCA2 and FANCD2. The C terminus of BRCA2 is therefore required for the functional interaction of BRCA2 and FANCD2 in chromatin. Taken together, our results demonstrate that monoubiquitination of FANCD2, which is regulated by the FA pathway, promotes BRCA2 loading into chromatin complexes. These complexes appear to be required for normal homology-directed DNA repair.

scholarly journals BRUCE regulates DNA double-strand break response by promoting USP8 deubiquitination of BRIT1

2015 ◽  
Vol 112 (11) ◽  
pp. E1210-E1219 ◽  
Author(s):  
Chunmin Ge ◽  
Lixiao Che ◽  
Jinyu Ren ◽  
Raj K. Pandita ◽  
Jing Lu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Genomic Stability ◽  
Strand Break ◽  
Breast Cancer Susceptibility ◽  
Breast Cancer Susceptibility Gene ◽  
Dna Double Strand Breaks ◽  
Apoptosis Protein ◽  
Chromatin Relaxation

The DNA damage response (DDR) is crucial for genomic integrity. BRIT1 (breast cancer susceptibility gene C terminus-repeat inhibitor of human telomerase repeat transcriptase expression), a tumor suppressor and early DDR factor, is recruited to DNA double-strand breaks (DSBs) by phosphorylated H2A histone family, member X (γ-H2AX), where it promotes chromatin relaxation by recruiting the switch/sucrose nonfermentable (SWI–SNF) chromatin remodeler to facilitate DDR. However, regulation of BRIT1 recruitment is not fully understood. The baculovirus IAP repeat (BIR)-containing ubiquitin-conjugating enzyme (BRUCE) is an inhibitor of apoptosis protein (IAP). Here, we report a non-IAP function of BRUCE in the regulation of the BRIT1–SWI–SNF DSB-response pathway and genomic stability. We demonstrate that BRIT1 is K63 ubiquitinated in unstimulated cells and that deubiquitination of BRIT1 is a prerequisite for its recruitment to DSB sites by γ-H2AX. We show mechanistically that BRUCE acts as a scaffold, bridging the ubiquitin-specific peptidase 8 (USP8) and BRIT1 in a complex to coordinate USP8-catalyzed deubiquitination of BRIT1. Loss of BRUCE or USP8 impairs BRIT1 deubiquitination, BRIT1 binding with γ-H2AX, the formation of BRIT1 DNA damage foci, and chromatin relaxation. Moreover, BRUCE-depleted cells display reduced homologous recombination repair, and BRUCE-mutant mice exhibit repair defects and genomic instability. These findings identify BRUCE and USP8 as two hitherto uncharacterized critical DDR regulators and uncover a deubiquitination regulation of BRIT1 assembly at damaged chromatin for efficient DDR and genomic stability.

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