Ubiquitin-like proteins in the DNA damage response: the next generation

Abstract

DNA suffers constant insult from a variety of endogenous and exogenous sources. To deal with the arising lesions, cells have evolved complex and coordinated pathways, collectively termed the DNA damage response (DDR). Importantly, an improper DDR can lead to genome instability, premature ageing and human diseases, including cancer as well as neurodegenerative disorders. As a crucial process for cell survival, regulation of the DDR is multi-layered and includes several post-translational modifications. Since the discovery of ubiquitin in 1975 and the ubiquitylation cascade in the early 1980s, a number of ubiquitin-like proteins (UBLs) have been identified as post-translational modifiers. However, while the importance of ubiquitin and the UBLs SUMO and NEDD8 in DNA damage repair and signalling is well established, the roles of the remaining UBLs in the DDR are only starting to be uncovered. Herein, we revise the current status of the UBLs ISG15, UBL5, FAT10 and UFM1 as emerging co-regulators of DDR processes. In fact, it is becoming clear that these post-translational modifiers play important pleiotropic roles in DNA damage and/or associated stress-related cellular responses. Expanding our understanding of the molecular mechanisms underlying these emerging UBL functions will be fundamental for enhancing our knowledge of the DDR and potentially provide new therapeutic strategies for various human diseases including cancer.

UBL5/Hub1: An Atypical Ubiquitin-Like Protein with a Typical Role as a Stress-Responsive Regulator

“…It appears that splicing of not all but specific introns are affected; the phenomenon is similar to Hub1 s intron-specific splicing regulation observed in yeasts [10,17,27,46]. Particularly in UBL5-deficient cells, the first intron of Sororin, a cohesion protection factor, is retained, while splicing of other introns of the same gene is unaffected [45,47]. The intron retention results in remarkable loss of Sororin protein and a decrease in the load of the protection factor onto chromatin upon mitotic exit [45].…”

More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond

“…As a consequence, components of the ubiquitin/UBL systems represent attractive drug targets for treating these diseases [9]. Although the involvement of ubiquitin, SUMO and NEDD8 in genotoxic stress responses is well established [3,10,11], the roles of the remaining UBLs in this regard are only starting to emerge [12,13]. Indeed, while ISG15 has primarily been associated with antiviral immune responses [14,15], additional non-canonical roles are starting to be uncovered.…”

“…ISG15 comparison with selected ubiquitin/UBLs, ubiquitin-like domains and across (A) Phylogeny of ubiquitin (Ub), ubiquitin-like proteins (UBLs) and Ub/UBL domains fused to human proteins. Genome stability associations are highlighted in green and apply to the following in addition to ISG15: Ub [3,10], Parkin [47][48][49][50], NEDD8 [11], UBTD1 [51], FAT10 [12], SF3A1 [52], RAD23A and RAD23B [53], TMUB1 (aka HOPS) [54][55][56], UBL5 (aka HUB1) [12], UHRF1 [57][58][59], ELOB (aka TCEB2) [60], USP48 [61,62], ATG12 [63], BAG6 [64], RBCK1 [65], BAG1 [66,67], [68], UFM1 [12], UBQLN4 [69], SUMO1, SUMO2 and SUMO3 [70]; sequence similarity to ubiquitin highlighted in the outermost ring ranging from GABARAP (9.59%) in red over a white midpoint to (A) Phylogeny of ubiquitin (Ub), ubiquitin-like proteins (UBLs) and Ub/UBL domains fused to human proteins. Genome stability associations are highlighted in green and apply to the following in addition to ISG15: Ub [3,10], Parkin [47][48][49][50], NEDD8 [11], UBTD1 [51], FAT10 [12], SF3A1 [52], RAD23A and RAD23B [53], TMUB1 (aka HOPS)…”

“…Activated p53 then binds to p53-responsive elements (p53REs) for transcriptional activation of target genes (e.g., BAX, p21 and PUMA) that modulate cell-cycle arrest, senescence and/or apoptosis [148][149][150]. ISG15 expression has been linked in different ways to p53-mediated cellular responses [12,88,104,107,144,[151][152][153].…”

“…(A) Phylogeny of ubiquitin (Ub), ubiquitin-like proteins (UBLs) and Ub/UBL domains fused to human proteins. Genome stability associations are highlighted in green and apply to the following in addition to ISG15: Ub[3,10], Parkin[47][48][49][50], NEDD8[11], UBTD1[51], FAT10[12], SF3A1[52], RAD23A and RAD23B[53], TMUB1 (aka HOPS)[54][55][56], UBL5 (aka HUB1)[12], UHRF1[57][58][59], ELOB (aka TCEB2)[60], USP48[61,62], ATG12[63], BAG6[64], RBCK1[65], BAG1[66,67], HERPUD1[68],…”