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Review
. 2019 Jul 4:6:51.
doi: 10.3389/fmolb.2019.00051. eCollection 2019.

The Cajal Body Protein WRAP53β Prepares the Scene for Repair of DNA Double-Strand Breaks by Regulating Local Ubiquitination

Sofie Bergstrand  1 , Eleanor M O'Brien  2 , Marianne Farnebo  1   2
Affiliations
Review

The Cajal Body Protein WRAP53β Prepares the Scene for Repair of DNA Double-Strand Breaks by Regulating Local Ubiquitination

Sofie Bergstrand et al. Front Mol Biosci. .

Abstract

Proper repair of DNA double-strand breaks is critical for maintaining genome integrity and avoiding disease. Modification of damaged chromatin has profound consequences for the initial signaling and regulation of repair. One such modification involves ubiquitination by E3 ligases RNF8 and RNF168 within minutes after DNA double-strand break formation, altering chromatin structure and recruiting factors such as 53BP1 and BRCA1 for repair via non-homologous end-joining (NHEJ) and homologous recombination (HR), respectively. The WD40 protein WRAP53β plays an essential role in localizing RNF8 to DNA breaks by scaffolding its interaction with the upstream factor MDC1. Loss of WRAP53β impairs ubiquitination at DNA lesions and reduces downstream repair by both NHEJ and HR. Intriguingly, WRAP53β depletion attenuates repair of DNA double-strand breaks more than depletion of RNF8, indicating functions other than RNF8-mediated ubiquitination. WRAP53β plays key roles with respect to the nuclear organelles Cajal bodies, including organizing the genome to promote associated transcription and collecting factors involved in maturation of the spliceosome and telomere elongation within these organelles. It is possible that similar functions may aid also in DNA repair. Here we describe the involvement of WRAP53β in Cajal bodies and DNA double-strand break repair in detail and explore whether and how these processes may be linked. We also discuss the possibility that the overexpression of WRAP53β detected in several cancer types may reflect its normal participation in the DNA damage response rather than oncogenic properties.

Keywords: Cajal body; DNA repair; RNF8; WD40; WRAP53β; cancer; chromatin modification; ubiquitin.

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Figures

Figure 1
Figure 1
(A) Schematic illustration of the different WRAP53β complexes, their localization and function. Note: scaRNA and TERC are RNA molecules. (B) Schematic illustration of the domains, binding, phosphorylation and ubiquitination sites in the WRAP53β protein. The sites for post-translational modifications were obtained from PhosphoSitePlus on April 17, 2019. The location of WD40 repeats were predicted using the WD40-repeat protein Structures Predictor (Wu et al., ; Wang et al., , ; Ma et al., 2019); (WDSP, May 2nd 2019): WD40 1 (amino acid residues 159–197), WD40 2 (residues 207–259), WD40 3 (residues 266–305), WD40 4 (residues 313–354), WD40 5 (residues 358–397), WD40 6 (residues 402–442), WD40 7 (residues 450–510). (C) Schematic view of the functions of WRAP53β in Cajal bodies, at the break site and in surrounding chromatin. Ubiquitin-dependent recruitment of DNA repair factors occurs at regions flanking the break site. WRAP53β binds γH2AX and also scaffolds the interaction between MDC1 and RNF8, which is important for the recruitment of RNF8 to DNA breaks. Once there, RNF8 and RNF168 ubiquitinate proteins at damaged chromatin, which stimulates recruitment of downstream factors 53BP1, RAD51, and BRCA1. BRCA1 forms several sub-complexes with different functions, of which the BRCA1-A complex (containing BRCA1, RAP80, BRCC36, and additional proteins not discussed here) restrict resection. Recruitment to the break site appears to be ubiquitin-independent and the factors recruited here include XRCC4, which promotes NHEJ, or DNA break sensor proteins, such as the MRN complex that promote HR. Pools of WRAP53β and BRCA1 also locate at this site for reasons unknown. Functions performed by WRAP53β in Cajal bodies could potentially be performed at break sites. The recruitment of RAD51, a downstream protein of WRAP53β, to DNA lesions appears to occur via both ubiquitin-dependent and independent mechanisms.
Figure 2
Figure 2
(A) The frequency of genetic alterations in WRAP53 associated with various cancer types (minimum threshold of 2%) (From cBioPortal, accessed April 17, 2019). The numbers in parenthesis represent the number of patients analyzed. (B) Proposed model for the involvement of WRAP53β and the DNA damage response in the development of cancer. Aberrant cell proliferation may cause replication stress, formation of DNA double-strand breaks and activation of the DNA damage response. Overexpression of WRAP53β as part of the response stimulates repair, growth arrest and/or apoptosis, but some damaged cells may escape (e.g., due to downregulation of WRAP53β), leading to genomic instability and potential progression into cancer.
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