New insights into abasic site repair and tolerance

Abstract

Thousands of apurinic/apyrimidinic (AP or abasic) sites form in each cell, each day. This simple DNA lesion can have profound consequences to cellular function, genome stability, and disease. As potent blocks to polymerases, they interfere with the reading and copying of the genome. Since they provide no coding information, they are potent sources of mutation. Due to their reactive chemistry, they are intermediates in the formation of lesions that are more challenging to repair including double-strand breaks, interstrand crosslinks, and DNA protein crosslinks. Given their prevalence and deleterious consequences, cells have multiple mechanisms of repairing and tolerating these lesions. While base excision repair of abasic sites in double-strand DNA has been studied for decades, new interest in abasic site processing has come from more recent insights into how they are processed in single-strand DNA. In this review, we discuss the source of abasic sites, their biological consequences, tolerance mechanisms, and how they are repaired in double and single-stranded DNA.

Keywords: Abasic site; Base excision repair; DNA-protein crosslinks; Genome stability; HMCES.

Fig. 1.

Mechanisms of AP site formation. A. Potential sources of AP site formation. B. Destabilization of N-glyosidic bond after base damage generates AP site. Spontaneous or catalyzed deamination of cytosine generates uracil. Subsequent action of UDG produces an AP site.

Fig. 2.

Consequences of unrepaired AP sites. AP sites (in center) react to form stable (pink) or transient (blue) DNA-protein crosslinks (DPCs) (left), generate intrastrand crosslinks (ICLs) (top), stall DNA polymerases and RNA polymerases (right), and can cause strand breakage via β-elimination (bottom).

Fig. 3.

AP site repair in ssDNA. A. Translesion synthesis (TLS) polymerase bypass an AP lesion to promote error-prone damage tolerance. B. Fork reversal generates a four-way chicken foot structure that can facilitate template switching or excision repair. C. Template switching using a strand invasion step can place a ssDNA AP lesion in the context of dsDNA for error-free bypass and repair.

Fig. 4.

New mechanisms of AP site recognition and repair in ssDNA. A. Model of Shu-mediated error-free damage tolerance of AP site. Shu complex binding to an AP site promotes RAD51 filament formation and template switching using the sister chromatid. BER is used to repair AP site post-replicatively. B. HMCES initiates repair of AP sites by forming a DNA-protein crosslink to AP site in ssDNA especially in the context of DNA replication. The HMCES-AP site DPC prevents endonuclease cleavage and TLS bypass. The mechanisms by which the HMCES-DPC is ultimately repaired remain unknown.