RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO

Hoege, Carsten; Pfander, Boris; Moldovan, George‐Lucian; Pyrowolakis, George; Jentsch, Stefan

doi:10.1038/nature00991

Cited by 2,003 publications

(2,672 citation statements)

References 52 publications

Supporting

Mentioning

2,557

Contrasting

Unclassified

Order By: Relevance

“…In yeast and mammalian cells, monoubiquitination of PCNA occurs on the conserved Lys 164 residue and is required for TLS function [6][7][8] . Accordingly, the increase in monoubiquitinated PCNA observed after knockdown of USP1 by siRNA requires Lys 164, as the mutation of this residue to arginine abrogated PCNA ubiquitin conjugation (Fig.…”

Section: Uv Damage Degrades Usp1 and Increases Pcna Monoubiquitinationmentioning

confidence: 99%

“…Protein monoubiquitination regulates the rescue of stalled DNA replication forks -an important cellular process required for cell survival 5 . The E2 ubiquitin conjugating enzyme RAD6 and the E3 ligase RAD18 are conserved in both yeast and human and they coordinate and activate the monoubiquitination of PCNA in response to UV damage or stalled replication forks [6][7][8] . Recent studies have shown that polη, a specialized TLS polymerase, is recruited to the replication fork through a specific interaction with monoubiquitinated PCNA 7 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Regulation of monoubiquitinated PCNA by DUB autocleavage

et al. 2006

View full text Add to dashboard Cite

Monoubiquitination is a reversible post-translational protein modification that has an important regulatory function in many biological processes, including DNA repair. Deubiquitinating enzymes (DUBs) are proteases that are negative regulators of monoubiquitination, but little is known about their regulation and contribution to the control of conjugated-substrate levels. Here, we show that the DUB ubiquitin specific protease 1 (USP1) deubiquitinates the DNA replication processivity factor, PCNA, as a safeguard against error-prone translesion synthesis (TLS) of DNA. Ultraviolet (UV) irradiation inactivates USP1 through an autocleavage event, thus enabling monoubiquitinated PCNA to accumulate and to activate TLS. Significantly, the site of USP1 cleavage is immediately after a conserved internal ubiquitin-like diglycine (Gly-Gly) motif. This mechanism is reminiscent of the processing of precursors of ubiquitin and ubiquitin-like modifiers by DUBs. Our results define a regulatory mechanism for protein ubiquitination that involves the signal-induced degradation of an inhibitory DUB.Monoubiquitination is a highly regulated process that is conserved in all eukaryotes 1,2 and controls a broad range of cellular functions, including DNA repair. Protein monoubiquitination is a reversible post-translational event that can be influenced by the opposing activities of a ubiquitin E3 ligase and a deubiquitinating enzyme (DUB), similar to the regulation of protein phosphorylation by kinases and phosphatases 3,4 . Protein monoubiquitination regulates the rescue of stalled DNA replication forks -an important cellular process required for cell survival 5 . The E2 ubiquitin conjugating enzyme RAD6 and the E3 ligase RAD18 are conserved in both yeast and human and they coordinate and activate the monoubiquitination of PCNA in response to UV damage or stalled replication forks [6][7][8] . Recent studies have shown that polη, a specialized TLS polymerase, is recruited to the replication fork through a specific interaction with monoubiquitinated PCNA 7 . The deployment of TLS polymerases during replication ensures timely bypass of the diverse DNA lesions encountered by the replication fork. Although many TLS polymerases are intrinsically mutagenic, polη allows replication past UV-damaged bases with high fidelity 9-11 . Thus, a model has emerged in which polη binds to monoubiquitinated PCNA and ensures accurate (error-free) replicative bypass of UV lesions. However, other (error-prone) TLS polymerases (such as polι and Rev1) have recently been shown to rely on monoubiquitinated PCNA for their function 12,13 . How cells limit PCNA monoubiquitination and the unwanted deployment of polη and/or other error-prone TLS polymerases in the absence or presence of extrinsic DNA damage during the synthesis of DNA in S phase is not known.In humans, protein deubiquitination is controlled by a family of approximately 95 distinct DUB enzymes 14,15 but the function of most of these proteins is unknown. DUBs are cysteine proteases that cleave ubiquitin fro...

show abstract

Section: Uv Damage Degrades Usp1 and Increases Pcna Monoubiquitinationmentioning

confidence: 99%

mentioning

confidence: 99%

Regulation of monoubiquitinated PCNA by DUB autocleavage

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Nevertheless, the exact molecular mechanisms underlying nicotine's effect on DNA repair and DNA damage tolerance remain largely unknown and controversial. Recent evidence strongly implicates ubiquitination and sumoylation in DNA replication/repair and damage tolerance [22,50].…”

Section: Discussionmentioning

confidence: 99%

Nicotine coregulates multiple pathways involved in protein modification/degradation in rat brain

Kane

Konu

Jennie

et al. 2004

Molecular Brain Research

View full text Add to dashboard Cite

Previously, we used cDNA microarrays to demonstrate that the phosphatidylinositol and MAP kinase signaling pathways are regulated by nicotine in different rat brain regions. In the present report, we show that, after exposure to nicotine for 14 days, ubiquitin, ubiquitinconjugating enzymes, 20S and 19S proteasomal subunits, and chaperonin-containing TCP-1 protein (CCT) complex members are upregulated in rat prefrontal cortex (PFC) while being downregulated in the medial basal hypothalamus (MBH). In particular, relative to saline controls, ubiquitins B and C were upregulated by 33% and 47% ( Pb0.01), respectively, in the PFC. The proteasome beta subunit 1 (PSMB1) and 26S ATPase 3 (PSMC3) genes were upregulated in the PFC by 95% and 119% ( Pb0.001), respectively. In addition to the protein degradation pathway of the ubiquitin-proteasome complexes, we observed in the PFC an increase in the expression of small, ubiquitin-related modifiers (SUMO) 1 and 2 by 80% and 33%, respectively ( Pb0.001), and in 3 of 6 CCT subunits by up to 150% ( Pb0.0001). To a lesser extent, a change in the opposite direction was obtained in the expression of the same gene families in the MBH. Quantitative real-time RT-PCR was used to validate the microarray results obtained with some representative genes involved in these pathways. Taken together, our results suggest that, in response to systemic nicotine administration, the ubiquitin-proteasome, SUMO, and chaperonin complexes provide an intricate control mechanism to maintain cellular homeostasis, possibly by regulating the composition and signaling of target neurons in a region-specific manner. D

show abstract

“…This replacement of replicative with TLS polymerase is designated the "polymerase switch". A seminal paper by Jentsch and co-workers identified the central role of PCNA in the polymerase switch [23]. They showed that in S. cerevisiae, when the replication fork was blocked, in this case by damage inflicted by methyl methanesulfonate, PCNA became modified by ubiquitination on lysine-164.…”

Section: Recruitment To the Replication Forkmentioning

confidence: 99%

“…Further ubiquitin molecules were added in a lysine-63 linkage by the E2 heterodimer Mms2-Ubc13 and the E3 Rad5. It was proposed that mono-ubiquitination channelled the damage through an error-prone TLS pathway, whereas poly-ubiquitination channelled into an error-free pathway of damage avoidance [23,24]. This latter pathway has been postulated to involve a copy choice type of recombination involving template switching, but it is poorly understood and will not be discussed further.…”

Section: Recruitment To the Replication Forkmentioning

confidence: 99%

Translesion synthesis in mammalian cells

Lehmann

2006

Experimental Cell Research

100

View full text Add to dashboard Cite

DNA damage blocks the progression of the replication fork. In order to circumvent the damaged bases, cells employ specialised low stringency DNA polymerases, which are able to carry out translesion synthesis (TLS) past different types of damage. The five polymerases used in TLS in human cells have different substrate specificities, enabling them to deal with many different types of damaged bases. PCNA plays a central role in recruiting the TLS polymerases and effecting the polymerase switch from replicative to TLS polymerase. When the fork is blocked PCNA gets ubiquitinated. This increases its affinity for the TLS polymerases, which all have novel ubiquitin-binding motifs, thereby facilitating their engagement at the stalled fork to effect TLS.

show abstract

RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO

Cited by 2,003 publications

References 52 publications

Regulation of monoubiquitinated PCNA by DUB autocleavage

Regulation of monoubiquitinated PCNA by DUB autocleavage

Nicotine coregulates multiple pathways involved in protein modification/degradation in rat brain

Translesion synthesis in mammalian cells

Contact Info

Product

Resources

About