Historical perspective on the DNA damage response

Abstract

The DNA damage response (DDR) has been broadly defined as a complex network of cellular pathways that cooperate to sense and repair lesions in DNA. Multiple types of DNA damage, some natural DNA sequences, nucleotide pool deficiencies and collisions with transcription complexes can cause replication arrest to elicit the DDR. However, in practice, the term DDR as applied to eukaryotic/mammalian cells often refers more specifically to pathways involving the activation of the ATM (ataxia-telangiectasia mutated) and ATR (ATM-Rad3-related) kinases in response to double-strand breaks or arrested replication forks, respectively. Nevertheless, there are distinct responses to particular types of DNA damage that do not involve ATM or ATR. In addition, some of the aberrations that cause replication arrest and elicit the DDR cannot be categorized as direct DNA damage. These include nucleotide pool deficiencies, nucleotide sequences that can adopt non-canonical DNA structures, and collisions between replication forks and transcription complexes. The response to these aberrations can be called the genomic stress response (GSR), a term that is meant to encompass the sensing of all types of DNA aberrations together with the mechanisms involved in coping with them. In addition to fully functional cells, the consequences of processing genomic aberrations may include mutagenesis, genomic rearrangements and lethality.

Keywords: ATM; ATR; DNA damage response; DNA repair; Genomic stress response; SOS response.

Figure 1

Early model for the expected consequence if a replication fork encountered a single strand break in the DNA template strand. This was presented after the discovery of repair replication but prior to the discovery of Okazaki fragments and discontinuous lagging strand synthesis. Adapted from P. Hanawalt, “The UV sensitivity of bacteria; its relation to the DNA replication cycle” Photochem.Photobiol. 5: 1–12 (1966).

Figure 2

Examples of threats that may initiate a genomic stress response (GSR) and some modes for their processing, with deleterious consequences or undamaged cells. Base damage includes alkylation, oxidation and deamination (e.g. cytosine to uracil), repairable by BER, although also some alkylations are reversible by alkyltransferases or dioxygenases. Abasic sites and strand breaks are intermediates in BER, but abasic sites are also generated by spontaneous depurination. Mismatch repair deals with errors during replication and small loops (that can arise through strand slippage). CPDs and bulky adducts such as polycyclic aromatic hydrocarbons (PAH) are repaired by NER. Non-canonical DNA structures are also subject to processing by repair systems even though formed in natural DNA sequences. Transcription may be arrested at lesions or unusual DNA structures to require processing by transcription-coupled repair (TCR). A translocating or blocked RNA polymerase may be encountered by a replication fork, requiring special processing. Double strand breaks (DSB) or interstrand cross-links (ICL) are the most serious types of damage, usually requiring several repair pathways in concert for their restitution, and inevitably resulting in activation of the GSR. A single strand break is a serious threat to a replication fork, but also to a transcription complex. The outcomes from processing these multiple threats require intricate regulatory systems, which include the cell cycle checkpoints triggered by ATM and ATR activation.