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Interplay between Ubiquitin, SUMO, and Poly(ADP-Ribose) in the Cellular Response to Genotoxic Stress.

Pellegrino S, Altmeyer M - Front Genet (2016)

Bottom Line: Cells employ a complex network of molecular pathways to cope with endogenous and exogenous genotoxic stress.This multilayered response ensures that genomic lesions are efficiently detected and faithfully repaired in order to safeguard genome integrity.Both ubiquitylation and SUMOylation can lead to extensive chain-like protein modifications, a feature that is shared with yet another DNA damage-induced PTM, the modification of proteins with poly(ADP-ribose) (PAR).

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Mechanisms of Disease, University of Zurich Zürich, Switzerland.

ABSTRACT
Cells employ a complex network of molecular pathways to cope with endogenous and exogenous genotoxic stress. This multilayered response ensures that genomic lesions are efficiently detected and faithfully repaired in order to safeguard genome integrity. The molecular choreography at sites of DNA damage relies heavily on post-translational modifications (PTMs). Protein modifications with ubiquitin and the small ubiquitin-like modifier SUMO have recently emerged as important regulatory means to coordinate DNA damage signaling and repair. Both ubiquitylation and SUMOylation can lead to extensive chain-like protein modifications, a feature that is shared with yet another DNA damage-induced PTM, the modification of proteins with poly(ADP-ribose) (PAR). Chains of ubiquitin, SUMO, and PAR all contribute to the multi-protein assemblies found at sites of DNA damage and regulate their spatio-temporal dynamics. Here, we review recent advancements in our understanding of how ubiquitin, SUMO, and PAR coordinate the DNA damage response and highlight emerging examples of an intricate interplay between these chain-like modifications during the cellular response to genotoxic stress.

No MeSH data available.


Related in: MedlinePlus

Chain-like modifications build up dynamic DNA repair compartments that orchestrate the DNA damage response (DDR). (A) In response to DNA damage, and subsequent to the MRN/ATM/MDC1-driven phosphorylation of histone variant H2AX, ubiquitylation of H1 and H2B by RNF8 and RNF168, respectively, synergizes with ubiquitin-dependent extraction of proteins from the damaged chromatin to promote the recruitment of 53BP1 and its downstream effectors. (B) SUMOylation by PIAS1 and PIAS4 further enhances ubiquitin conjugation around DNA break sites. (C) Poly(ADP-ribosyl)ation (PARylation) by PARPs generates a recruitment platform for a plethora of PAR-binding proteins, including various transcription factors (TFs), DNA- and RNA-binding proteins (DRBPs), and a set of intrinsically disordered proteins (IDPs). P, phosphorylation; Me, methylation; Ub, ubiquitylation; S, SUMOylation; A, ADP-ribosylation; M, MRE11; R, RAD50; N, NBS1.
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Figure 1: Chain-like modifications build up dynamic DNA repair compartments that orchestrate the DNA damage response (DDR). (A) In response to DNA damage, and subsequent to the MRN/ATM/MDC1-driven phosphorylation of histone variant H2AX, ubiquitylation of H1 and H2B by RNF8 and RNF168, respectively, synergizes with ubiquitin-dependent extraction of proteins from the damaged chromatin to promote the recruitment of 53BP1 and its downstream effectors. (B) SUMOylation by PIAS1 and PIAS4 further enhances ubiquitin conjugation around DNA break sites. (C) Poly(ADP-ribosyl)ation (PARylation) by PARPs generates a recruitment platform for a plethora of PAR-binding proteins, including various transcription factors (TFs), DNA- and RNA-binding proteins (DRBPs), and a set of intrinsically disordered proteins (IDPs). P, phosphorylation; Me, methylation; Ub, ubiquitylation; S, SUMOylation; A, ADP-ribosylation; M, MRE11; R, RAD50; N, NBS1.

Mentions: Chromosome breaks are among the most toxic DNA lesions and two major repair pathways evolved to deal with DSBs. The non-homologous end-joining (NHEJ) pathway is independent of intact template DNA sequences and can re-ligate broken DNA ends throughout the cell cycle. In contrast, faithful repair by homologous recombination (HR) depends on an undamaged template DNA and is thus restricted to the S/G2 phases of the cell cycle when sister chromatids are available. While NHEJ is generally considered error-prone due to the risk of nucleotide loss from DNA ends, HR is considered to be more accurate due to template-based repair. The choice between NHEJ and HR is tightly controlled, and imbalances in its regulation can lead to genome instability and accelerate cancer development (Chapman et al., 2012; Aparicio et al., 2014). Interestingly, the recruitment of several key repair pathway choice mediators to DNA break sites depends on local ubiquitin conjugations (Messick and Greenberg, 2009; Pinder et al., 2013). Indeed, one of the central players of repair pathway choice is the ubiquitin-sensing genome caretaker protein 53BP1, whose recruitment to DSBs requires the consecutive action of the ubiquitin E3 ligases RNF8 and RNF168 (Panier and Boulton, 2014). In a concerted manner, and initiated by upstream phosphorylation of the histone variant H2AX, RNF8, and RNF168 ubiquitylate histones H1 and H2A, respectively, and thereby provide a landing platform for 53BP1 (Mattiroli et al., 2012; Fradet-Turcotte et al., 2013; Gatti et al., 2015; Thorslund et al., 2015). 53BP1 in turn assembles the effector proteins RIF1, PTIP, Artemis, and MAD2L2/REV7 to limit the extent of DNA end resection and thereby channel repair toward NHEJ (Figure 1A) (Callen et al., 2013; Chapman et al., 2013; Di Virgilio et al., 2013; Escribano-Diaz et al., 2013; Zimmermann et al., 2013; Wang et al., 2014; Boersma et al., 2015; Xu et al., 2015). Of note, the functions of 53BP1 and its effectors are required for the hypersensitivity of HR-defective cancer cells to inhibitors of PAR polymerases (Lord and Ashworth, 2016), thus linking the consequences of compromised PARylation to the effects of a ubiquitin-dependent anti-resection barrier under pathological repair pathway choice conditions.


Interplay between Ubiquitin, SUMO, and Poly(ADP-Ribose) in the Cellular Response to Genotoxic Stress.

Pellegrino S, Altmeyer M - Front Genet (2016)

Chain-like modifications build up dynamic DNA repair compartments that orchestrate the DNA damage response (DDR). (A) In response to DNA damage, and subsequent to the MRN/ATM/MDC1-driven phosphorylation of histone variant H2AX, ubiquitylation of H1 and H2B by RNF8 and RNF168, respectively, synergizes with ubiquitin-dependent extraction of proteins from the damaged chromatin to promote the recruitment of 53BP1 and its downstream effectors. (B) SUMOylation by PIAS1 and PIAS4 further enhances ubiquitin conjugation around DNA break sites. (C) Poly(ADP-ribosyl)ation (PARylation) by PARPs generates a recruitment platform for a plethora of PAR-binding proteins, including various transcription factors (TFs), DNA- and RNA-binding proteins (DRBPs), and a set of intrinsically disordered proteins (IDPs). P, phosphorylation; Me, methylation; Ub, ubiquitylation; S, SUMOylation; A, ADP-ribosylation; M, MRE11; R, RAD50; N, NBS1.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4835507&req=5

Figure 1: Chain-like modifications build up dynamic DNA repair compartments that orchestrate the DNA damage response (DDR). (A) In response to DNA damage, and subsequent to the MRN/ATM/MDC1-driven phosphorylation of histone variant H2AX, ubiquitylation of H1 and H2B by RNF8 and RNF168, respectively, synergizes with ubiquitin-dependent extraction of proteins from the damaged chromatin to promote the recruitment of 53BP1 and its downstream effectors. (B) SUMOylation by PIAS1 and PIAS4 further enhances ubiquitin conjugation around DNA break sites. (C) Poly(ADP-ribosyl)ation (PARylation) by PARPs generates a recruitment platform for a plethora of PAR-binding proteins, including various transcription factors (TFs), DNA- and RNA-binding proteins (DRBPs), and a set of intrinsically disordered proteins (IDPs). P, phosphorylation; Me, methylation; Ub, ubiquitylation; S, SUMOylation; A, ADP-ribosylation; M, MRE11; R, RAD50; N, NBS1.
Mentions: Chromosome breaks are among the most toxic DNA lesions and two major repair pathways evolved to deal with DSBs. The non-homologous end-joining (NHEJ) pathway is independent of intact template DNA sequences and can re-ligate broken DNA ends throughout the cell cycle. In contrast, faithful repair by homologous recombination (HR) depends on an undamaged template DNA and is thus restricted to the S/G2 phases of the cell cycle when sister chromatids are available. While NHEJ is generally considered error-prone due to the risk of nucleotide loss from DNA ends, HR is considered to be more accurate due to template-based repair. The choice between NHEJ and HR is tightly controlled, and imbalances in its regulation can lead to genome instability and accelerate cancer development (Chapman et al., 2012; Aparicio et al., 2014). Interestingly, the recruitment of several key repair pathway choice mediators to DNA break sites depends on local ubiquitin conjugations (Messick and Greenberg, 2009; Pinder et al., 2013). Indeed, one of the central players of repair pathway choice is the ubiquitin-sensing genome caretaker protein 53BP1, whose recruitment to DSBs requires the consecutive action of the ubiquitin E3 ligases RNF8 and RNF168 (Panier and Boulton, 2014). In a concerted manner, and initiated by upstream phosphorylation of the histone variant H2AX, RNF8, and RNF168 ubiquitylate histones H1 and H2A, respectively, and thereby provide a landing platform for 53BP1 (Mattiroli et al., 2012; Fradet-Turcotte et al., 2013; Gatti et al., 2015; Thorslund et al., 2015). 53BP1 in turn assembles the effector proteins RIF1, PTIP, Artemis, and MAD2L2/REV7 to limit the extent of DNA end resection and thereby channel repair toward NHEJ (Figure 1A) (Callen et al., 2013; Chapman et al., 2013; Di Virgilio et al., 2013; Escribano-Diaz et al., 2013; Zimmermann et al., 2013; Wang et al., 2014; Boersma et al., 2015; Xu et al., 2015). Of note, the functions of 53BP1 and its effectors are required for the hypersensitivity of HR-defective cancer cells to inhibitors of PAR polymerases (Lord and Ashworth, 2016), thus linking the consequences of compromised PARylation to the effects of a ubiquitin-dependent anti-resection barrier under pathological repair pathway choice conditions.

Bottom Line: Cells employ a complex network of molecular pathways to cope with endogenous and exogenous genotoxic stress.This multilayered response ensures that genomic lesions are efficiently detected and faithfully repaired in order to safeguard genome integrity.Both ubiquitylation and SUMOylation can lead to extensive chain-like protein modifications, a feature that is shared with yet another DNA damage-induced PTM, the modification of proteins with poly(ADP-ribose) (PAR).

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Mechanisms of Disease, University of Zurich Zürich, Switzerland.

ABSTRACT
Cells employ a complex network of molecular pathways to cope with endogenous and exogenous genotoxic stress. This multilayered response ensures that genomic lesions are efficiently detected and faithfully repaired in order to safeguard genome integrity. The molecular choreography at sites of DNA damage relies heavily on post-translational modifications (PTMs). Protein modifications with ubiquitin and the small ubiquitin-like modifier SUMO have recently emerged as important regulatory means to coordinate DNA damage signaling and repair. Both ubiquitylation and SUMOylation can lead to extensive chain-like protein modifications, a feature that is shared with yet another DNA damage-induced PTM, the modification of proteins with poly(ADP-ribose) (PAR). Chains of ubiquitin, SUMO, and PAR all contribute to the multi-protein assemblies found at sites of DNA damage and regulate their spatio-temporal dynamics. Here, we review recent advancements in our understanding of how ubiquitin, SUMO, and PAR coordinate the DNA damage response and highlight emerging examples of an intricate interplay between these chain-like modifications during the cellular response to genotoxic stress.

No MeSH data available.


Related in: MedlinePlus