DNA-damage repair; the good, the bad, and the ugly

Abstract

Organisms have developed several DNA-repair pathways as well as DNA-damage checkpoints to cope with the frequent challenge of endogenous and exogenous DNA insults. In the absence or impairment of such repair or checkpoint mechanisms, the genomic integrity of the organism is often compromised. This review will focus on the functional consequences of impaired DNA-repair pathways. Although each pathway is addressed individually, it is essential to note that cross talk exists between repair pathways, and that there are instances in which a DNA-repair protein is involved in more than one pathway. It is also important to integrate DNA-repair process with DNA-damage checkpoints and cell survival, to gain a better understanding of the consequences of compromised DNA repair at both cellular and organismic levels. Functional consequences associated with impaired DNA repair include embryonic lethality, shortened life span, rapid ageing, impaired growth, and a variety of syndromes, including a pronounced manifestation of cancer.

Figure 1

DNA-repair pathways. Several DNA-repair pathways exist and deal with various types of DNA insults. These pathways include (1) the direct reversal pathway, (2) the MMR pathway, (3) the NER pathway, (4) the BER pathway, (5) the HR pathway, and (6) the NHEJ pathway.

Figure 2

Examples of human syndromes and disorders associated with defective DNA-damage repair. Impaired MMR pathway leads to the hereditary HNPCC. Mutations of certain human NER genes have been associated with syndromes and disorders including the XP, CS, and TTD. MAP, a rare disorder, has been shown associated with mutations of the BER gene MUTYH. Various human syndromes and disorders have been associated with defects of the HR pathway. They include ATLD, NBS, BS, WS and RTS. Mutations of certain human genes involved in NHEJ lead to the SCID or RS-SCID.