Choreographing the Double Strand Break Response: Ubiquitin and SUMO Control of Nuclear Architecture

Harding, Shane M.; Greenberg, Roger A.

doi:10.3389/fgene.2016.00103

Cited by 17 publications

(16 citation statements)

References 139 publications

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“…In contrast to the wealth of phosphorylation targets in the DDR, the number of known ubiquitylation substrates at DSB sites is small (Harding and Greenberg, 2016). While K63-linked ubiquitylation mediates functional alterations of the target protein, K48linked ubiquitin chains mark target proteins for proteasomemediated degradation (Walczak et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors

Jachimowicz

Beleggia

Isensee

et al. 2019

Cell

114

147

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Graphical Abstract Highlights d Homozygous UBQLN4 germline mutations lead to a genome instability syndrome d UBQLN4 removes ubiquitylated MRE11 from damaged chromatin to curtail DSB resection d UBQLN4 overexpression represses HRR and promotes the use of NHEJ for DSB repair d UBQLN4 overexpression in tumors promotes PARP1 inhibitor sensitivity SUMMARY Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4overexpressing tumors.of selected pairs defined in a contrast matrix using the R library multcomp. Error bars represent SD of the mean for 3 replicate wells analyzed in one experiment. Each experiment was carried out twice. *p < 0.05. (N) Quantification of the relative comet tail moment (n = 100) derived from the neutral comet assays at the indicated time points. Error bars represent SD of the mean of the relative comet tail moment analyzed in n = 3 experiments.

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Section: Introductionmentioning

confidence: 99%

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors

Jachimowicz

Beleggia

Isensee

et al. 2019

Cell

114

147

View full text Add to dashboard Cite

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“…Despite the complexity, this is a fine-tuned process that brings each DDR protein to the protein conglomerates spanning DSB sites at the precise time and location to perform the ultimate task: smooth and streamlined DSB repair. The importance of tight regulation of protein ubiquitylation in this process has been noted (Harding and Greenberg, 2016; Lee et al, 2017; Panier and Durocher, 2013). A primary level of this regulation is the universal balance between the relevant E3 ligases and opposing deubiquitylating proteases (DUBs) (Pellegrino and Altmeyer, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Many players in the DSB response relocate to DSB sites, where they form large protein hubs (Lukas et al, 2011). These proteins typically undergo post-translational modifications (PTMs), primarily poly(ADP-ribosylation), phosphorylation, and modification by the ubiquitin family proteins, which set them up to operate in the DDR (Harding and Greenberg, 2016; Lee et al, 2017; Martin-Hernandez et al, 2017; Polo and Jackson, 2011; Shiloh and Ziv, 2013a; Wilson and Durocher, 2017). This massive protein recruitment is a highly structured process, in which the damage-induced PTMs often establish interactions among the proteins to help mobilize and correctly locate the next-in-line recruits.…”

Section: Introductionmentioning

confidence: 99%

“…Protein ubiquitylation at DSB sites is carried out by several E3 ubiquitin ligases and is critical for mobilizing chromatin dynamics at these sites, appropriate recruitment of DDR factors and, eventually, DSB repair (Harding and Greenberg, 2016; Lee et al, 2017). Indeed, extensive K48- and K63-linked ubiquitylations were observed at DSB sites (Lee et al, 2017; Meerang et al, 2011), but the number of documented ubiquitylation targets is limited and current consensual substrates are histones H2A, H2B and H1 (Harding and Greenberg, 2016; Lee et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, extensive K48- and K63-linked ubiquitylations were observed at DSB sites (Lee et al, 2017; Meerang et al, 2011), but the number of documented ubiquitylation targets is limited and current consensual substrates are histones H2A, H2B and H1 (Harding and Greenberg, 2016; Lee et al, 2017). Identification of the ubiquitin ligases that take part in the DDR is key to understanding ubiquitin-driven pathways in this network.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair

et al. 2018

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Summary Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning - the E3/E4 ubiquitin ligase, UBE4A. UBE4A’s recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end-resection at DSBs, and its abrogation leads to up-regulation of the highly mutagenic alternative end-joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning of the complex DDR network for accurate and balanced execution of DSB repair.

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Identifying UBA2 as a proliferation and cell cycle regulator in lung cancer A549 cells

Jiang

Fan

Zhang

et al. 2019

J of Cellular Biochemistry

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Ubiquitin activating enzyme 2 (UBA2) is a basic component of E1-activating enzyme in the SUMOylation system. Expression and function of UBA2 in human cancers are largely unknown. In this study we investigate UBA2 expression the function in human non-small-cell lung cancer. Immunochemistry study showed that UBA2 was overexpressed in cancer tissues (53.3%, 40 of 75) compared with normal lung tissues (14.3%, 4 of 28) (P < 0.05).Immunostaining of UBA2 was mainly detected in nucleus. Overexpression of UBA2 in cancer tissues was significantly associated with poor differentiation, large tumor size ( > 5.0 cm), higher T stages (T3 + 4), lymph node metastasis and advanced TNM stages (III + IV). In vitro study showed that UBA2 was expressed in A549, 95D, H1975, and H1299 cells. Knockdown of UBA2 in A549 cells significantly inhibited cancer cell proliferation and upregulated cancer cell apoptosis (P < 0.05). Cell cycle analysis showed that knockdown of UBA2 in A549 cell significantly increased the G1 and G2/M phase cells and reduced the S phase cells (P < 0.05). Gene expression profile after knockdown of UBA2 in A549 cells showed that the most related function was cell cycle, cell death and survival, and cellular growth and proliferation. Western blot analysis study showed that knockdown of UBA2 significantly inhibited expression of poly (ADP-ribose) polymerase 1, mini-chromosome maintenance 7 (MCM7), MCM2, MCM3 and MCM7. These results indicated that UBA2 was a critical cell cycle and proliferation regulator and may be a novel cancer marker in this malignant tumor. K E Y W O R D Scell cycle, non-small-cell lung cancer, proliferation, ubiquitin activating enzyme 2

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Choreographing the Double Strand Break Response: Ubiquitin and SUMO Control of Nuclear Architecture

Cited by 17 publications

References 139 publications

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors

The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair

Identifying UBA2 as a proliferation and cell cycle regulator in lung cancer A549 cells

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