The products of the yeast MMS2 and two human homologs (hMMS2 and CROC- 1) define a structurally and functionally conserved Ubc-like protein family

Xiao, Wei; Lin, Stanley L.; Broomfield, Stacey; Chow, Barbara L.; Yue, Wei

doi:10.1093/nar/26.17.3908

Cited by 95 publications

(81 citation statements)

References 58 publications

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“…Regardless of the mode of reaction, it is abundantly clear that the error-free DDT process is highly conserved in the entire eukaryotic kingdom, from yeast to human. Sequence and functional homologs of all proteins involved in error-free DDT, including Mms2 [140], Ubc13 [141] and Rad5 [142,143], have been found in mammals, plants and other higher eukaryotes [144,145]. For a few limited examples, suppression of the above genes resulted in phenotypes reminiscent of the corresponding yeast mutants [143,146,147].…”

Section: Error-free Ddtmentioning

confidence: 99%

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Andersen¹,

Xiao³

2007

Cell Res

184

187

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npg In addition to well-defined DNA repair pathways, all living organisms have evolved mechanisms to avoid cell death caused by replication fork collapse at a site where replication is blocked due to disruptive covalent modifications of DNA. The term DNA damage tolerance (DDT) has been employed loosely to include a collection of mechanisms by which cells survive replication-blocking lesions with or without associated genomic instability. Recent genetic analyses indicate that DDT in eukaryotes, from yeast to human, consists of two parallel pathways with one being error-free and another highly mutagenic. Interestingly, in budding yeast, these two pathways are mediated by sequential modifications of the proliferating cell nuclear antigen (PCNA) by two ubiquitination complexes Rad6-Rad18 and Mms2-Ubc13-Rad5. Damage-induced monoubiquitination of PCNA by Rad6-Rad18 promotes translesion synthesis (TLS) with increased mutagenesis, while subsequent polyubiquitination of PCNA at the same K164 residue by Mms2-Ubc13-Rad5 promotes error-free lesion bypass. Data obtained from recent studies suggest that the above mechanisms are conserved in higher eukaryotes. In particular, mammals contain multiple specialized TLS polymerases. Defects in one of the TLS polymerases have been linked to genomic instability and cancer. DNA damage toleranceIn the presence of spontaneous or carcinogen-induced DNA damage, living cells have to maintain and complete DNA synthesis or risk replication fork collapse. Since the process of DNA licensing is to ensure the genome is duplicated once and only once during each cell cycle, stalled or collapsed replication forks may not be able to restart, which often results in double-strand breaks (DSBs) and causes compromised genome integrity or cell death. In addition to highly conserved DNA repair pathways, all living organisms have evolved schemes to ensure continuation of DNA synthesis in the presence of damage. These schemes were originally termed DNA postreplication repair (PRR) due to observations of transient shortened nascent DNA structures following S phase in response to DNA damage. In bacteria and unicellular yeast, these shortened DNA segments can be measured by an alkaline sedimentation assay [1] or directly observed in electron micrographs [2]. In wild-type cells, these truncated DNA segments were restored to full length following a short recovery time. One typical experiment [1] involved the restoration of the nascent strand following UV exposure in nucleotide excision repair (NER)-deficient cells and was originally assumed to represent a mechanism of DNA repair. However, further investigation revealed that, although the nascent fragments were re-annealed, the original UV-induced pyrimidine dimers, which were responsible for the generation of single-strand gaps, often persisted in the genome [3,4]. It was argued that the replication-blocking lesion was not necessarily corrected, but rather transiently bypassed and carried over to the next generation. Perhaps it is more beneficial for the organi...

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Section: Error-free Ddtmentioning

confidence: 99%

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Andersen¹,

Xiao³

2007

Cell Res

184

187

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“…Xiao et al (21) isolated the human homolog of the S. cerevisiae MMS2 gene, designated hMMS2. The present study was designed to determine whether the hMMS2 gene plays a critical role in the ability of human cells to tolerate DNA damage, and if so, to identify the pathway in which it functions and determine the nature of the molecular events involved.…”

mentioning

confidence: 99%

Identification of a protein essential for a major pathway used by human cells to avoid UV- induced DNA damage

Xiao

McCormick

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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When DNA replication stalls at a fork-blocking lesion, cells use damage tolerance pathways to continue replication. One pathway, ''translesion synthesis,'' involves specialized DNA polymerases that can use damaged DNA as a template. Translesion synthesis can result in mutations (i.e., can be error-prone), but it can also be error-free. An alternative pathway has been hypothesized (sometimes called ''damage avoidance''), by which cells make temporary use of an undamaged copy of the blocked sequence as a template, i.e., the newly synthesized daughter strand of the sister duplex or the allelic copy. This pathway is error-free. Evidence of the use of the daughter strand of the sister duplex as a template in intact mammalian cells has not been available heretofore. To determine whether hMms2, a ubiquitin-conjugating enzyme-like protein, plays a critical role in such damage avoidance, a human fibroblast cell strain in which both error-prone translesion synthesis and error-free damage avoidance can be detected and quantified simultaneously, and several derivative strains in which expression of hMms2 protein had been eliminated or greatly decreased, were compared for their ability to avoid translesion synthesis past UV 254nm-induced DNA photoproducts. Loss of hMms2 protein eliminated the ability of the latter strains to use an allelic copy of a target gene for damage avoidance, i.e., to produce a wild-type gene from two nonfunctional allelic copies of that gene. Molecular analysis of the wild-type gene showed that this process involves gene conversion unassociated with crossing-over. That the loss of hMms2 also eliminated use of the daughter strand of the sister duplex as a template for damage avoidance could be inferred from the fact that the frequency of mutations induced by UV in the single copy HPRT gene of the derivative strains was significantly higher than that observed in the parental strain. These data indicate that hMMS2 is essential for human cells to carry out damage avoidance by using either type of homolog, and that damage avoidance and translesion synthesis are alternative pathways for tolerating fork-blocking photoproducts. D NA is constantly exposed to damaging agents. If the damage is not removed, e.g., by excision repair, before the onset of S-phase, certain kinds of lesions can block replication by the major DNA polymerase complex (1). The damage tolerance mechanisms developed by prokaryotic and eukaryotic cells to overcome such replication blocks fall into two categories: translesion synthesis and damage avoidance. Evidence suggests that translesion synthesis is a process in which specialized, distributive DNA polymerases take over for the major DNA polymerase complex to carry out DNA replication by using the damaged DNA as a template (2-5). After distributive incorporation of nucleotides past the damage, the major DNA replication complex resumes its replication activity. Translesion synthesis can be either ''error-prone'' or ''error-free,'' depending on such factors as the type of damage, its seque...

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“…The canonical uev-1 and ubc-13 do not suppress rpm-1: Biochemical studies of canonical UEV proteins in yeast and mammalian cells, such as Mms2 and Uev1A, respectively, have established that the UEV domain functions as an obligatory subunit for an active Ubc, Ubc13 Xiao et al 1998;Deng et al 2000). The Uev1A/Ubc13 E2 complex catalyzes Lys63 poly-ubiquitin chain formation (Hofmann and Pickart 1999;Vandemark et al 2001).…”

Section: Uev-3 Functions In Dlk-1 Pathway 139mentioning

confidence: 99%

A Ubiquitin E2 Variant Protein Acts in Axon Termination and Synaptogenesis in Caenorhabditis elegans

et al. 2010

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In the developing nervous system, cohorts of events regulate the precise patterning of axons and formation of synapses between presynaptic neurons and their targets. The conserved PHR proteins play important roles in many aspects of axon and synapse development from C. elegans to mammals. The PHR proteins act as E3 ubiquitin ligases for the dual-leucine-zipper-bearing MAP kinase kinase kinase (DLK MAPKKK) to regulate the signal transduction cascade. In C. elegans, loss-of-function of the PHR protein RPM-1 (Regulator of Presynaptic Morphology-1) results in fewer synapses, disorganized presynaptic architecture, and axon overextension. Inactivation of the DLK-1 pathway suppresses these defects. By characterizing additional genetic suppressors of rpm-1, we present here a new member of the DLK-1 pathway, UEV-3, an E2 ubiquitin-conjugating enzyme variant. We show that uev-3 acts cell autonomously in neurons, despite its ubiquitous expression. Our genetic epistasis analysis supports a conclusion that uev-3 acts downstream of the MAPKK mkk-4 and upstream of the MAPKAPK mak-2. UEV-3 can interact with the p38 MAPK PMK-3. We postulate that UEV-3 may provide additional specificity in the DLK-1 pathway by contributing to activation of PMK-3 or limiting the substrates accessible to PMK-3. C HEMICAL synapses are specialized cellular junctions that enable neurons to communicate with their targets. An electrical impulse causes calcium channel opening and consequently stimulates synaptic vesicles in the presynaptic terminals to fuse at the plasma membrane. Neurotransmitter activates receptors on the postsynaptic membrane and triggers signal transduction in the target cell. For this communication to occur efficiently, the organization of the proteins within these juxtaposed pre-and postsynaptic terminals must be tightly regulated ( Jin and Garner 2008). Previous studies in Caenorhabditis elegans have identified RPM-1, a member of the conserved PHR (Pam/Highwire/RPM-1) family of proteins, as an important regulator for the synapse (Schaefer et al. 2000;Zhen et al. 2000). Recent functional studies of other PHR proteins have shown that they are also required for a number of steps during nervous system development including axon guidance, growth, and termination (Wan et al. 2000;D'souza;Bloom et al. 2007;Grill et al. 2007;Lewcock et al. 2007;Li et al. 2008).The signaling cascades regulated by the PHR proteins have been identified using genetic modifier screens (Diantonio et al. 2001;Liao et al. 2004;Nakata et al. 2005;Collins et al. 2006) and biochemical approaches (Grill et al. 2007;Wu et al. 2007). These studies reveal that a major function of PHR proteins is to act as ubiquitin E3 ligases ( Jin and Garner 2008). In C. elegans, RPM-1 (Regulator of Presynaptic Morphology-1) regulates the abundance of its substrate, the dualleucine-zipper-bearing MAP kinase kinase kinase (DLK MAPKKK), and controls the activity of the MAP kinase cascade composed of three additional kinases, MAPKK MKK-4, p38 MAPK PMK-3, and MAPKAPK MAK-2 (Nakata ...

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The products of the yeast MMS2 and two human homologs (hMMS2 and CROC- 1) define a structurally and functionally conserved Ubc-like protein family

Cited by 95 publications

References 58 publications

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Identification of a protein essential for a major pathway used by human cells to avoid UV- induced DNA damage

A Ubiquitin E2 Variant Protein Acts in Axon Termination and Synaptogenesis in Caenorhabditis elegans

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