Protein degradation pathways regulate the functions of helicases in the DNA damage response and maintenance of genomic stability

Abstract

Degradation of helicases or helicase-like proteins, often mediated by ubiquitin-proteasomal pathways, plays important regulatory roles in cellular mechanisms that respond to DNA damage or replication stress. The Bloom's syndrome helicase (BLM) provides an example of how helicase degradation pathways, regulated by post-translational modifications and protein interactions with components of the Fanconi Anemia (FA) interstrand cross-link (ICL) repair pathway, influence cell cycle checkpoints, DNA repair, and replication restart. The FANCM DNA translocase can be targeted by checkpoint kinases that exert dramatic effects on FANCM stability and chromosomal integrity. Other work provides evidence that degradation of the F-box DNA helicase (FBH1) helps to balance translesion synthesis (TLS) and homologous recombination (HR) repair at blocked replication forks. Degradation of the helicase-like transcription factor (HLTF), a DNA translocase and ubiquitylating enzyme, influences the choice of post replication repair (PRR) pathway. Stability of the Werner syndrome helicase-nuclease (WRN) involved in the replication stress response is regulated by its acetylation. Turning to transcription, stability of the Cockayne Syndrome Group B DNA translocase (CSB) implicated in transcription-coupled repair (TCR) is regulated by a CSA ubiquitin ligase complex enabling recovery of RNA synthesis. Collectively, these studies demonstrate that helicases can be targeted for degradation to maintain genome homeostasis.

Figure 1

Proteolytic degradation of DNA helicases and helicase-like proteins. Protein interactions (A) and post-translational modifications (B) of DNA helicases or helicase-like proteins affect their stability. In a number of cases, protein interactions or post-translational modifications of helicase proteins affect their ubiquitylation which in turn influences stability via a proteasome degradation pathway. Post-translational modification of helicase proteins by ubiquitylating enzymes are listed in Table 1. See text for details. Blue, helicase or helicase-like protein; Maroon, helicase-interacting DNA repair and/or replication protein; Green, protein kinase; Yellow, acetyltransferase. The asterisk in Panel A indicates that BRCA1 has an intrinsic ubiquitin ligase activity. The asterisks in Panel B indicate the involvement of phosphorylation by protein kinases (NEK11, CHK1, PlK1) or acetylation by acetyltransferases (p300, CBP) in helicase protein stability.

Figure 2

Dynamics of BLM helicase ubiquitylation govern its stability and recruitment to stalled replication forks and suppression of sister chromatid exchange. See text for details.

Figure 3

RMI1/2 is important for BLM stability, phosphorylation, and its role in double Holliday Junction dissolution. See text for details.

Figure 4

BLM interaction with FANCJ (A) or FANCD2 (B) prevents its degradation and provides resistance to replication stress and timely restart of stalled replication forks. See text for details.

Figure 5

MlB1 ubiquitin ligase and NEK11 kinase influence BLM stability which has outcomes for non-homologous end-joining and suppression of sister chromatid exchange. Certain aspects of this model are debated. See text for details.

Figure 6

Chk1 phosphorylation of BLM prevents its degradation by Cullin E3 ubiquitin ligase, enabling BLM to collaborate with PICH and resolve chromosomal bridges. See text for details.

Figure 7

Adenovirus infection promotes E1b55k/E4orf6 ubiquitin ligase-mediated mediated BLM degradation. See text for details.

Figure 8

FANCM phosphorylation controls FANCM stability and its role at stalled replication forks. See text for details.

Figure 9

FBH1 proteolysis is governed by its interaction with PCNA during the UV-induced DNA damage response. See text for details.

Figure 10

Werner syndrome helicase-nuclease (WRN) acetylation affects its stability, catalytic functions, and subcellular localization. See text for details.

Figure 11

HLTF degradation enables translesion polymerase bypass of alkylated DNA damage. See text for details.

Figure 12

CSA-associated ubiquitin ligase insures CSB degradation enabling RNA synthesis recovery in the transcription-coupled repair pathway. See text for details.