Diseases associated with defective responses to DNA damage

Abstract

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 identified, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways.

Figure 1.

Different genetic defects in DNA-PKcs. Schematic representation of human DNA-PKcs (in purple) showing the relative positioning of the FAT, FATC, and PI3K-calalytic kinase domains. The spontaneous deletions (del) observed within DNA-PKcs in Jack Russell terriers, Arabian horse, and mouse are shown in gray, all of which involve loss of the catalytic PI3K-active site.

Figure 2.

PNKP, its substrates and structure. (A) PNKP functions to clean up damaged termini at single-strand breaks to reconstitute the 3′-OH and 5′-phosphate (P) ends required for ligation. Some of the typical damaged termini requiring processing are shown here in red. The 3′-P, 5′-OH and phosphoglycolate termini are a consequence of ROS-induced DNA damage. The 3′-deoxyribose phosphates are produced by AP endonuclease action or by the AP lyase activity of certain DNA glycosylases. Topo I-cleavable complexes (CC) require the combined action of ubiquitin-dependent proteosomal degradation and TDP1 action to remove the covalently bound Topo I from DNA to repair the underlying strand nick. (B) Schematic representation of PNKP showing the juxtaposition of the phosphatase and kinase domains. The FHA domain is an important phosphoprotein-binding domain implicated in binding to CK2 phosphorylation sites on XRCC1 and XRCC4. MCSZ-patient mutations are shown in red.

Figure 3.

TCR under specific contexts. UV photoproducts (red) create a localized distortion in the DNA helix prompting recognition and removal by nucleotide excision repair (NER). In actively transcribing regions of the genome, UV lesions create a block to RNA polymerase II (RNA Pol II [gray]), temporarily inhibiting RNA synthesis (blue) prompting engagement of transcription-coupled repair (TCR). In normal cells, stalled RNA Pol II is ubiquitinated in an ERCC6/ERCC8-dependent manner. The combined action of the ERCC6/ERCC8 and UVSSA/USP7 complexes somehow coordinate to enable stalled ubiquitinated RNA Pol II to be repositioned, thereby allowing access to the lesion for the NER machinery to remove the lesion. In the UVSSA-UV^s situation, both ERCC6 and the stalled RNA Pol II remain ubiquitinated, likely prompting their degradation by the proteasome. Therefore, no repair occurs by rapid TCR and the lesion is left to be dealt with by global genome NER (GGR). In the context of Cockayne syndrome, ubiquitination of the stalled RNA Pol II does not occur and the polymerase remains stalled at the lesion, likely generating a very strong apoptotic signal owing to the failure to recover transcription.

Figure 4.

ICL repair. An interstrand cross-link (ICL) poses a serious problem for replication and transcription. Here, two replication forks converge on an ICL (red). One of the forks is extended toward the ICL, whereas the other remains stalled and stabilized. The FA pathway is engaged and monoubiquitylated-FANC-D2 (D2-Ubq) is localized to the ICL. Excision of one strand occurs (gray), likely involving ERCC1-XPF and/or SLX4, depending on the context, generating a monoadducted lesion. Translesion synthesis (TLS) is engaged to allow bypass of the adducted base in the template strand (black). The resultant DNA double-strand break is thought to be repaired by homologous recombination, whereas the monoadduct is removed by NER.

Figure 5.

Pathogenic defects in RNF168. Schematic representation of RNF168 showing the relative positions of the RING domain and the ubiquitin-binding domains (MIU1 and MIU2). The RIDDLE-syndrome-associated RNF168 defects are shown on the left-hand side, whereas the nonsense RNF168 defect described by Devgan and colleagues is shown on the right-hand side.