Ubiquitin-Binding Domains in Y-Family Polymerases Regulate Translesion Synthesis

By Marzena Bienko, C. Green, N. Crosetto, F. Rudolf, G. Zapart, Barry J. Coull, P. Kannouche, G. Wider, Matthias Peter, A. Lehmann and 2 more. Science, 2005

733 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8c3831ee21d2ab5fde91dc845685d71340280563

How researchers see this paper

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In Cell Biology

1. D. Komander
2. M. Rapé
3. D. Finley
4. Alberto Ciccia
5. Ivan Dikic
6. Stephen J. Elledge
7. Tony Pawson
8. A. Bowie

In Molecular Biology

1. D. Komander
2. Ivan Dikic
3. M. Rapé
4. Stephen J. Elledge
5. J. Harper
6. Tony Pawson
7. K. Husnjak
8. Alberto Ciccia

Citations in the corpus

• The DNA Damage Response: Making it safe to play with knives (2010, background): “Indeed, TLS polymerases associate with monoubiquitinated PCNA through UBZ or UBM ubiquitin binding motifs, which then provide an additional PCNA interaction surface required to target TLS polymerases to sites of DNA damage (Bienko et al., 2005; Ulrich and Walden, 2010).”
• Y-family DNA polymerases and their role in tolerance of cellular DNA damage (2012, unknown): “4 ), which increase their affinity for ubiquitylated PCNA at the site of blocked replicatio”
• Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. (2009, background): “These observations are clearly distinct from the NZF domain of HDAC6 (Boyault et al., 2006), the UBM of Poli (Bienko et al., 2005), and the UBA domain of hRad23A, which bind to all diubiquitin chains (linear, Lys63, and Lys48) (Figure 1A).”
• Regulation of the Rev1–pol ζ complex during bypass of a DNA interstrand cross‐link (2015, unknown): “In addition to a PCNA-interacting motif, TLS polymerases contain ubiquitin-binding domains, which are thought to stimulate their interaction with ubiquitylated PCNA at the fork (Bienko et al , 2005).”
• Ubiquitin-binding domains — from structures to functions (2009, background): “, which serves as a ubiquitin-binding adaptor protein in the endoplasmic reticulum-associated degradation ( ERAD ) pathway, and the ubiquitin-binding ZnF (UBZ) domain, which is present in translesion synthesis polymerases”
• Reading protein modifications with interaction domains (2006, background): “However, some UBDs ? such as ubiquitin-binding motifs (UBMs) of translesion DNA polymerases and the Rabex-5 ubiquitin-binding zinc finger (RUZ) domain of Rabex-5, a Rab5 guanine nucleotide-exchange factor ? bind to sites on ubiquitin that are distinct from the Ile44 patc”
• Proteasome subunit Rpn13 is a novel ubiquitin receptor (2008, methodology): “Fluorescence spectrophotometry was used to determine hRpn13's affinity for monoubiquitin and diubiquitin, since hRpn13 (1-150) contains two tryptophan residues and ubiquitin none.”
• Targeting the ubiquitin system in cancer therapy (2009, background): “Their specific roles can be exemplified by regulation of the double-strand DNA repair pathways (the UIMs in RAP80), translesion synthesis (TLS) pathways (the UBM and UBZ domains in TLS polymerases”
• The ubiquitin code. (2012, background): “Among many examples, the inhibitor the NF-κ B transcription factor, I κ B α , is degraded after modification / 17 15 . o r Lys48-linked chains by SCF (172, 173).”
• A novel function of DNA polymerase ζ regulated by PCNA (2006, background): “In addition, PolZ possesses ubiquitin-binding domains that mediate its interaction with ubiquitinated PCNA (Bienko et al, 2005; Plosky et al, 2006).”
• PCNA, the maestro of the replication fork. (2007, unknown): “Ubiquitin-binding domains were found in Y-family TLS polymerases (Polη, Polι, Rev1) (Bienko et al., 2005), and these domains in addition to their PCNA-binding motifs (PIP boxes of Polη and Polι but a BRCT domain in Rev1; Table S1) are required for recruiting them specifically to monoubiquitylated…”
• Post-translational modifications in signal integration (2010, background): “Monoubiquitinated PCNA can recruit error-prone translesion DNA polymerases (also called Y-family polymerases) through their UBDs in order to bypass a damaged DNA sit”
• The DNA damage response: ten years after. (2007, background): “The ssDNA-RPA complex then plays two critical roles: it recruits the ATR protein through its regulatory subunit ATRIP (Zou and Elledge, 2003), and it recruits and activates the Rad17 clamp loader which then loads the PCNA-related 911 (Rad9Rad1-Hus1) complex onto DNA (Yang and Zou, 2006).”