Multi-Faceted Roles of ERCC1-XPF Nuclease in Processing Non-B DNA Structures

Abstract

Genetic instability can result from increases in DNA damage and/or alterations in DNA repair proteins and can contribute to disease development. Both exogenous and endogenous sources of DNA damage and/or alterations in DNA structure (e.g., non-B DNA) can impact genome stability. Multiple repair mechanisms exist to counteract DNA damage. One key DNA repair protein complex is ERCC1-XPF, a structure-specific endonuclease that participates in a variety of DNA repair processes. ERCC1-XPF is involved in nucleotide excision repair (NER), repair of DNA interstrand crosslinks (ICLs), and DNA double-strand break (DSB) repair via homologous recombination. In addition, ERCC1-XPF contributes to the processing of various alternative (i.e., non-B) DNA structures. This review will focus on the processing of alternative DNA structures by ERCC1-XPF.

Keywords: DNA repair; ERCC1-XPF; genetic instability; non-B DNA structure.

Figure 1.

Schematic of non-B DNA structures. (A) R-loop, (B) D-loop, (C) hairpin/stem-loop and slipped DNA (formed at inverted repeat sequences), (D) cruciform DNA formed at inverted repeat sequences, (E) Z-DNA (formed at alternating purine-pyrimidine sequences), (F) H-DNA (formed at polypurine and polypyrimidine DNA sequences with mirror symmetry), (G) G-quadruplex (G4) DNA (formed at G_≥3N_xG_≥3N_xG_≥3N_xG_≥3 DNA sequences). Adapted from Wang and Vasquez (2014) [12].

Figure 2.

Proposed mechanism for the cleavage of R-loops. ERCC1-XPF and XPG are recruited to R-loops and can cleave the junctions between the R-loop and the duplex DNA. ERCC1-XPF can cleave both the template and non-template strand, ultimately resulting in DSBs. Adapted from Sollier et al. (2014) [31] and Tian and Alt (2000) [30].

Figure 3.

Cleavage of D-loops by Rad10-Rad1. (A) Rad10-Rad1 cleaves the D-loop to create a nicked Holliday junction or a single Holliday junction. (B) Rad10-Rad1 cleaves 3′ overhangs creating a double Holliday junction. (C) Removal of the 3′ flap of newly synthesized DNA. DNA synthesized past the point of homology is removed by Rad10-Rad1. (D) Removal of non-homologous 3′ tails to initiate DNA synthesis. (E) Removal of non-homologous 3′ tail on the non-invading strand. Cleavage by Rad10-Rad1 is represented by scissors. Adapted from Giaccherini and Gaillard (2021) [34], Mazón et al. (2012) [35], and Lyndaker and Alani (2009) [38].

Figure 4.

Cleavage of hairpin and cruciform structures by ERCC1-XPF. (A) ERCC1-XPF cleaves the stem at the 5′ side of hairpins, while XPG cleaves the 3′ side. (B) ERCC1-XPF cleaves cruciform loops. Cleavage of both loops may result in DSBs that can be processed in an error-generating fashion, resulting in genetic instability. Adapted from de Laat et al. (1998) [51], Sijbers et al. (1996) [52], and Lu et al. (2015) [53].

Figure 5.

Mechanism of mutagenic Z-DNA processing. MSH2-MSH3 binds to the junction between B-DNA and Z-DNA. ERCC1-XPF is then recruited to the site where it can cleave within and/or surrounding the Z-DNA structure, creating a DSB, which can be repaired in an error-generating fashion, leading to genetic instability. Adapted from McKinney et al. (2020) [68].

Figure 6.

Replication-dependent and replication-independent cleavage of H-DNA. (A) In replicationin-dependent processing of H-DNA, ERCC1-XPF and XPG are recruited to H-DNA. ERCC1-XPF cleaves the loop between Hoogsteen hydrogen-bonded strands, and XPG cleaves ssDNA near the DNA duplex. (B) In replication-dependent processing of H-DNA, the structure can impede progressing replication complexes. FEN1 can cleave H-DNA to prevent mutations by allowing for continuous replication. However, ERCC1-XPF and XPG may also cleave this structure, which can then be processed in a mutagenic fashion. Adapted from Zhao et al. (2018) [74].

Figure 7.

Cleavage of G-quadruplex (G4) DNA by ERCC1-XPF. G4 structure formation may occur during cellular processes, such as replication, causing fork stalling. ERCC1-XPF may cleave G4 structures to allow replication and/or repair to continue. Adapted from Li et al. (2019) [102].