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Replication and Repair* Ann Rose§ Department of Medical Genetics, University of British Columbia, Vancouver, Canada

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Replication and Repair* Ann Rose§ Department of Medical Genetics, University of British Columbia, Vancouver, Canada Replication and repair* Ann Rose§ Department of Medical Genetics, University of British Columbia, Vancouver, Canada Table of Contents 1. Introduction ............................................................................................................................1 2. The FA repair pathway ............................................................................................................. 4 3. Interstrand crosslinks (ICLs) ...................................................................................................... 4 4. G-rich secondary structures ....................................................................................................... 5 5. Checkpoint activation ............................................................................................................... 6 6. Double strand breaks (DSBs) ..................................................................................................... 6 7. Single strand breaks (SSBs) ....................................................................................................... 6 8. Cohesins ................................................................................................................................7 9. Telomere maintenance .............................................................................................................. 7 10. Meiosis ................................................................................................................................7 11. Mutators ...............................................................................................................................8 12. Chromatin modifications ......................................................................................................... 8 13. Looking Forward ................................................................................................................... 9 14. Summary ..............................................................................................................................9 15. Acknowledgments .................................................................................................................. 9 16. References ............................................................................................................................9 1. Introduction Integrity of genetic information is essential to both individual health and reproductive capacity. The Caenorhabditis elegans model system provides an opportunity not only to investigate the components of the various repair pathways and the pathway interactions, but also to study the role of repair in different developmental stages. A number of different DNA repair pathways respond to damage dependent upon the nature of the damage, type of cell, stage of development, and genomic location, for example, at the telomeres (Astin et al., 2008; Clejan et al., 2006; reviewed in Lans and Vermeulen, 2011). It is well known, for example, that the response to DNA double strand breaks (DSBs) in the proliferating premeiotic germline differs from that during meiosis or embryonic cleavage, and from somatic cell replication (Vermezovic et al., 2012; Couteau and Zetka, 2011; Lans et al., 2010; McLellan et al., 2009; Pontier and Tijsterman, 2009; Lee et al., 2007; Holway et al., 2006; Weidhaas et al., 2006). For example, differences between somatic and germ line cell response to DNA damage were examined and * Edited by Thomas Blumenthal, Last revised: February 14, 2013. Published December 4, 2014. This chapter should be cited as: Rose A. Replication and repair (December 4, 2014), WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/ wormbook.1.54.2, http://www.wormbook.org. Copyright: © 2014 Ann Rose. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. §To whom correspondence should be addressed: [email protected] 1 Replication and repair molecular mechanisms for somatic cell resistance to DNA damage-induced cell death described (Vermezovic et al., 2012). As an animal system, C. elegans provides a useful model to more fully understand the integration of the types of repair that occur in response to DNA damage in different cell types during growth and development (See the developmental profile of repair gene RNA in Figure 1). Figure 1. Expression profile during C. elegans development. Expression profile clustering of a set of DNA repair genes using nearest neighbor hierarchical clustering of the normalized RNA-seq data from the modEncode website is shown (www.modencode.org). The cluster analysis has been modified by hand somewhat to aggregate some groupings. The top axis is the developmental profile from fertilization to adult hermaphrodite. There is a clear change in the expression pattern at column six at the onset of gastrulation (150 min post fertilization), marked by a purple bar. A darker purple bar marks the mid-first larval stage. The green bars indicate mutant strains used. The darker green is a germline-minus strain, JK1107. Adjacent to the left are mid-larval females and young pre-gravid adult hermaphrodites. Clustering and figure prepared by Dr. Jeffrey Chu, University of British Columbia. 2 Replication and repair Since the previous version of this chapter (DNA repair), there has been an explosion of research using C. elegans to study many aspects of DNA repair and several reviews have been published (Table 1). In this chapter, the focus will be on research in the past few years beginning with the use of C. elegans in the study of the Fanconi Anemia (FA) repair pathway (reviewed in Youds et al., 2009; see also Jones and Rose, 2012). The FA pathway (see below) is involved in identifying replication blocks that can result from either unresolved DNA secondary structures (Kruisselbrink et al., 2008; Youds et al., 2006; Cheung et al., 2002) or from interstrand crosslinks (ICLs) (reviewed in McVey, 2010; Youds et al., 2009; and more generally in Kottemann and Smogorzewska, 2013; Deans and West, 2011). Repair involves translesion synthesis (TLS) and homologous recombination (HR) repair but not nonhomologous endjoining (NHEJ) (Youds et al., 2006). A key component of the FA pathway, FCD-2/FANCD2, is involved in directing repair towards error-free HR and away from error-prone NHEJ. This important choice has been shown to be under genetic control and regulated by FANCD2, which binds to DNA lesions and recruits repair proteins. In C. elegans, genetic interaction analysis demonstrated that elimination of NHEJ by inhibition of LIG4 suppressed the repair defects of Fcd-2 mutants (Adamo et al., 2010). In both C. elegans and human cells (Adamo et al., 2010; Pace et al., 2010; reviewed in Bunting and Nussensweig, 2010), it was discovered that FANCD2 is required to prevent NHEJ, which can lead to chromosomal rearrangements that may be mutagenic and toxic to the cell. HR repair, on the other hand, is essentially error free and thus the more desirable pathway for faithful reproduction. Table 1: Reviews cited Topic Reference Fanconi anemia and ICL repair Youds et al., 2009 Jones and Rose, 2012 FA Repair in avian cells Takata et al., 2006 DOG-1/FANCJ and G4 DNA repair Maizels, 2008; Brosh, 2011 G4 DNA and human disease Wu and Brosh, 2010 Interstrand crosslink repair Kottemann and Smogorzewska, 2013; Deans and West, 2011; McVey, 2010 Chromatin modification at DSB Fischle, 2009 Double strand break repair Lemmens and Tijsterman, 2011; Pontier and Tijsterma, 2009 Phosphorylation in DSB repair Summers et al., 2011 Cohesion and DNA repair Sjögren and Strom, 2009; Watrin and Peters, 2006 C. elegans cohesins Wood et al., 2010 PARPs and synthetic lethality St-Laurent and Desnoyers, 2011; Helleday, 2011 Nucleotide excision repair Lans and Vermeulen, 2011 3 Replication and repair Table 2: Known components of the FA pathway in C. elegans Reference (also Component Gene Function www.wormbase.org) Ko et al., 2008; Petalcorin et al., BRC-2 Loads RAD-51 2007; Martin et al., 2005 FCD-2 Promotes HR repair Adamo et al., 2010; Lee et al., 2007; Collis et al., 2006 FNCI-1 Required for FCD-2 focus formation Lee, K.Y. et al., 2010 DOG-1 Unwinds G-tracts Youds et al., 2008; Youds et al., 2006; Cheung et al., 2002 FNCM-1 Required for ubiquitination of FCD-2 Lee, K.Y. et al., 2010 RFS-1 RAD-51, paralog in HR repair Yanowitz, 2008; Ward et al., 2007 SLX-4 endonuclease in HR repair Saito et al., 2009 2. The FA repair pathway The Fanconi anemia pathway is so-named because of a genetic disease in humans first described by G. Fanconi (1927, in Lobitz and Velleuer, 2006). In humans, FA is a rare recessive genetic disorder characterized by bone marrow failure resulting in anemia and accompanied by developmental abnormalities and cancer susceptibility as a result of subsequent genome instability (www.fanconi.org). Diagnosis involves cellular hypersensitivity to DNA crosslinking agents and more recently whole genome sequencing (WGS) (Ameziane et al., 2012). The pathway consists of a core complex of proteins that mono-ubiquinate FANC D2 and I, which then localize to sites of DNA-damage and promote HR repair. There are currently 15 genetic subtypes that have been described (A, B, C, D1 [BRCA2], D2, E, F, G, I, J, L, M, N, O and P) (Ameziane et al., 2012; reviewed in Kottemann and Smogorzewska, 2013; Deans and West, 2011). In C. elegans as in other species, the FA
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