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.
Highlights
Specialty section: This article was submitted to Cellular Biochemistry, a section of the journal Frontiers in Molecular Biosciences
RNAs are transcribed from sites of DNA damage (Francia et al, 2012; Wei et al, 2012; Michelini et al, 2017; Bonath et al, 2018), which can hybridize with the damaged DNA (Ohle et al, 2016; Lu et al, 2018), be processed by DICER and DROSHA (Francia et al, 2012; Michelini et al, 2017; Lu et al, 2018) or become methylated by N6-adenosine-methyltransferase kDa subunit (METTL3) (Xiang et al, 2017), thereafter, regulating damage repair
We have suggested that WD40-encoding RNA antisense to p53 (WRAP53β) has oncogenic properties (Mahmoudi et al, 2011), we believe that this is a misinterpretation of the data, which instead reflects participation of WRAP53β in the DNA damage response (Figure 2B)
Summary
Structural organization within the nuclear space contributes significantly to functional regulation (Misteli, 2005; Nunez et al, 2009; Van Bortle and Corces, 2012). For Cajal bodies, this nucleation occurs at specific genomic loci, including genes encoding small nuclear (sn)RNAs, small nucleolar (sno)RNAs, small Cajal body-specific (sca)RNAs and histones (Frey and Matera, 1995, 2001; Smith et al, 1995; Machyna et al, 2013). When transcribed, these loci are brought together in a transcriptional center within the Cajal body that accelerates RNA production (Sawyer et al, 2016a,b; Wang et al, 2016). WRAP53β may stimulate transcription of RNA from the break site and/or its processing or concentrate repair factors into specialized foci to accelerate necessary reactions
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