Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Diseases Associated with Defective Responses to DNA Damage Mark O’Driscoll Human DNA Damage Response Disorders Group Genome Damage and Stability Centre, University of Sussex, Brighton, East Sussex BN1 9RQ, United Kingdom Correspondence: [email protected] Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identi- fied, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways. he link between DNA damage, mutagenesis, sense XP represents a paradigm of a DNA repair Tand malignant transformation is long estab- disorder with a clear pathological link between lished. A logical extension is that a congenital genotype and phenotype (Cleaver et al. 2009). defect in a fundamental DNA repair pathway, As our knowledge of the complexity of ge- such as nucleotide excision repair (NER), would nome stability pathways has evolved, coupled be anticipated to be associated with a pro- with the explosive technical advances in molec- nounced cancer predisposition syndrome. In- ular and cellular biology, more and more hu- deed this is well known to be the case consid- man disorders caused by defects in components ering xeroderma pigmentosum (XP) (Cleaver that constitute the genome stability network 1968, 1969, 1970). In most XP subtypes, the continue to be described. At the most funda- devastatingly overt .1000-fold elevated risk of mental level, identification of these conditions developing basal and squamous cell carcinomas enables future accurate molecular diagnosis on sun-exposed areas of the skin is directly at- (Raffan et al. 2011). This has relevance for as- tributable to a failure to remove highly muta- sociated comorbidities and is vital for informed genic solar ultraviolet (UV) radiation-induced counseling of the parents, not just for family DNA photoproducts from the genome. In this planning and recurrence risk analysis, but can Editors: Errol C. Friedberg, Stephen J. Elledge, Alan R. Lehmann, Tomas Lindahl, and Marco Muzi-Falconi Additional Perspectives on DNA Repair, Mutagenesis, and Other Responses to DNA Damage available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a012773 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a012773 1 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press M. O’Driscoll assuage destructive feelings of maternal/pater- examples of some of the novel disorders that nal guilt and bring to an end what is often a have been described since 2005. I will first re- protracted and extremely stressful journey to view disorders of DNA repair pathways, includ- ascertain a clinical diagnosis (Raymond et al. ing those of nonhomologous DNA end joining 2010; Evans et al. 2011; Baker et al. 2012). These (NHEJ), base excision repair (BER)–single- disorders can also help inform the biology of strand break repair (SSBR), NER, and homolo- genome stability. Their diverse and often unan- gous recombination (HR)–interstrand cross- ticipated clinical features can provide evidence link (ICL) repair, before highlighting disorders for previously unappreciated biological connec- associated with defects in the DNA damage-in- tions (Griffith et al. 2008; Rauch et al. 2008; duced signal transduction responses (phos- Huang-Doran et al. 2011). Furthermore, these phorylation and ubiquitination). insights can help optimize therapeutic strate- gies for these conditions along with more com- NOVEL DISORDERS OF NHEJ mon conditions such as cancer. For example, the application of nonmyeloablative condition- The mechanics of the NHEJ pathway are out- ing protocols for bone marrow transplantation lined in Chiruvella et al. (2013). Two disorders, to combat the severe anemia and lymphoid ma- one caused by deficiency of a novel component, lignancy in Fanconi anemia, or the use of re- the other by mutation of a well-known compo- duced intensity radiotherapy strategies to treat nent ofNHEJ,havebeendescribed recently.Cells lymphoma in ataxia telangiectasia patients have from both disorders show pronounced defects both been developed directly from our under- in DNA double-strand break repair (DSBR). standing the inherent sensitivity of cells from these patients to specific forms of DNA damage Cernunnos/XLF-SCID (Gennery et al. 2005; Resnick et al. 2005; Lavin 2008). The interest in developing specific inhib- NHEJ represents an important means of direct- itors toward “drug-able” targets that play key ly repairing DNA double-strand breaks (DSBs) roles in DNA repair and the DNA damage re- by a resealing process not dependent on the sponse, to increase the selective sensitivity of availability of a homologous DNA strand. One tumor cells toward conventional DNA-damag- of the primary functions of NHEJ is the repair of ing therapies such as radiotherapy and certain programmed DSBs in the immunoglobin (Ig) chemotherapies is currently an active area of and T-cell receptor (TCR) gene loci during the interest (Bryant and Helleday 2004; Helleday process of V(D)J recombination to form the et al. 2008; Evers et al. 2010; Helleday 2010). complete Ig and TCR repertoire of the immune Since 2005, there have been several nota- system (Lieber 2010). Indeed the known human ble descriptions of novel congenital disorders conditions defective in a core component of caused by defects in known, or more important- NHEJ, DNA ligase IV (LIG4) causing LIG4 syn- ly, novel components of several DNA repair and drome and Artemis (DCLRE1C) causing Art- DNA damage response pathways. These condi- SCID (severe combined immunodeficiency), tions have been identified via a combination of are associated with pronounced T- and B-cell approaches: candidate gene approaches coupled deficiencies (Moshous et al. 2001; O’Driscoll to educated guesswork based on known biolo- et al. 2001, 2004; O’Driscoll and Jeggo 2006). gy of a particular pathway; by classical homo- These patients suffer frequent infections from zygosity linkage analysis using consanguineous an early age, invariably presenting initially in families; and in recent years, by the growing the immunology clinic. Because of the DSB re- influence of next-generation whole exome se- pair defect and consequent ionizing radiation quencing. The latter approach, in particular, of- sensitivity of cells from these patients, these fers the tantalizing prospect of being able to conditions are denoted as radiosensitive (RS)- identify additional potential genetic defects us- SCID, distinguishing them from other more ing single affected patients. Here, I will review common causes of SCID such as RAG1/2or 2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a012773 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Diseases and Defective Responses to DNA Damage adenosine deaminase deficiency (Riballo et al. cleavage at the Ig and TCR loci. Failure to pro- 2004). cess these coding ends effectively results in SCID Understanding the cellularand clinical spec- (Moshous et al. 2001; Ma et al. 2002). trum of RS-SCID enabled the subsequent iden- Compound heterozygous mutations in tification of defects in what transpired to be a PRKDC, the gene encoding DNA-PKcs, were novel NHEJ component: Cernunnos/XRCC4- recently identified in a single case of RS-SCID like factor (XLF), caused by mutations in without associated developmental features such NHEJ1. Using a functional cDNA library-based as the microcephaly and growth delay seen complementation cloning strategy, Buck and in LIG4 syndrome and Cernunnos/XLF-SCID colleagues used fibroblasts from a series of pa- (van der Burg et al. 2009a,b). It is noteworthy in tients characterized by pronounced T- and B- this context that Artemis deficiency similarly is cell-minus SCID, growth retardation, and mi- not associated with developmental abnormali- crocephaly (phenotypes reminiscent of LIG4 ties (Moshous et al. 2001; Li et al. 2002). The syndrome), identifying multiple mutations in identification of this novel and long-predicted a novel gene they called Cernunnos (Buck et al. genetic defect (spontaneous DNA-PKcs defects 2006). In a complementary approach, Ahnesorg occur in Jack Russell terrier dogs, Arabian and colleagues showed that a previously unde- horses, and mice [Fig. 1]) is owing to a thorough scribed XRCC4 interactant they had identified analysis of the immunological profile of the af- (XLF; XRCC4-like factor) was defective in a fected case (Bosma et al. 1983; Peterson et al. well-characterized