The DNA Damage Response: Making It Safe to Play with Knives

The posttranslational modification with ubiquitin, a process referred to as ubiquitylation, controls almost every process in cells. Ubiquitin can be attached to substrate proteins as a single moiety or in the form of polymeric chains in which successive ubiquitin molecules are connected through specific isopeptide bonds. Reminiscent of a code, the various ubiquitin modifications adopt distinct conformations and lead to different outcomes in cells. Here, we discuss the structure, assembly, and function of this ubiquitin code.

The Ubiquitin Code

Ubiquitylation is a reversible protein modification that is implicated in many cellular functions. Recently, much progress has been made in the characterization of a superfamily of isopeptidases that remove ubiquitin: the deubiquitinases (DUBs; also known as deubiquitylating or deubiquitinating enzymes). Far from being uniform in structure and function, these enzymes display a myriad of distinct mechanistic features. The small number (<100) of DUBs might at first suggest a low degree of selectivity; however, DUBs are subject to multiple layers of regulation that modulate both their activity and their specificity. Due to their wide-ranging involvement in key regulatory processes, these enzymes might provide new therapeutic targets.

Breaking the chains: structure and function of the deubiquitinases.

https://www.cell.com/cell/pdf/S0092-8674(07)00594-6.pdf

PCNA, the Maestro of the Replication Fork

The DNA Damage Response: Ten Years After

Translesion synthesis (TLS) is the major pathway by which mammalian cells replicate across DNA lesions. Upon DNA damage, ubiquitination of proliferating cell nuclear antigen (PCNA) induces bypass of the lesion by directing the replication machinery into the TLS pathway. Yet, how this modification is recognized and interpreted in the cell remains unclear. Here we describe the identification of two ubiquitin (Ub)-binding domains (UBM and UBZ), which are evolutionarily conserved in all Y-family TLS polymerases (pols). These domains are required for binding of poleta and poliota to ubiquitin, their accumulation in replication factories, and their interaction with monoubiquitinated PCNA. Moreover, the UBZ domain of poleta is essential to efficiently restore a normal response to ultraviolet irradiation in xeroderma pigmentosum variant (XP-V) fibroblasts. Our results indicate that Ub-binding domains of Y-family polymerases play crucial regulatory roles in TLS.

https://science.sciencemag.org/content/sci/310/5755/1821.full.pdf

Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis.

Nuclear factor kappa B (NF-κB) is a key mediator of inflammation Unchecked NF-κB signalling can engender autoimmune pathologies and cancers Here, we show that Tax1-binding protein 1 (TAX1BP1) is a negative regulator of TNF-α- and IL-1β-induced NF-κB activation and that binding to mono- and polyubiquitin by a ubiquitin-binding Zn finger domain in TAX1BP1 is needed for TRAF6 association and NF-κB inhibition Mice genetically knocked out for TAX1BP1 are born normal, but develop age-dependent inflammatory cardiac valvulitis, die prematurely, and are hypersensitive to low doses of TNF-α and IL-1β TAX1BP1−/− cells are more highly activated for NF-κB than control cells when stimulated with TNF-α or IL-1β Mechanistically, TAX1BP1 acts in NF-κB signalling as an essential adaptor between A20 and its targets

/pdf/inflammatory-cardiac-valvulitis-in-tax1bp1-deficient-mice-13a64wfv2i.pdf

Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-κB activation

Translesion synthesis (TLS) is the major pathway by which mammalian cells replicate across DNA lesions. Upon DNA damage, ubiquitination of proliferating cell nuclear antigen (PCNA) induces bypass of the lesion by directing the replication machinery into the TLS pathway. Yet, how this modification is recognized and interpreted in the cell remains unclear. Here we describe the identification of two ubiquitin (Ub)–binding domains (UBM and UBZ), which are evolutionarily conserved in all Y-family TLS polymerases (pols). These domains are required for binding of polη and polι to ubiquitin, their accumulation in replication factories, and their interaction with monoubiquitinated PCNA. Moreover, the UBZ domain of polη is essential to efficiently restore a normal response to ultraviolet irradiation in xeroderma pigmentosum variant (XP-V) fibroblasts. Our results indicate that Ub-binding domains of Y-family polymerases play crucial regulatory roles in TLS.

Grzegorz Zapart

Papers

Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis.

Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-κB activation

Supporting Online Material for Ubiquitin-Binding Domains in Y-Family Polymerases Regulate Translesion Synthesis

CIN85 regulates the ability of MEKK4 to activate the p38 MAP kinase pathway