Beyond Nucleotide Excision Repair: The Importance of XPF in Base Excision Repair and Its Impact on Cancer, Inflammation, and Aging

Abstract

DNA repair involves various intricate pathways that work together to maintain genome integrity. XPF (ERCC4) is a structural endonuclease that forms a heterodimer with ERCC1 that is critical in both single-strand break repair (SSBR) and double-strand break repair (DSBR). Although the mechanistic function of ERCC1/XPF has been established in nucleotide excision repair (NER), its role in long-patch base excision repair (BER) has recently been discovered through the 5'-Gap pathway. This study briefly explores the roles of XPF in different pathways to emphasize the importance of XPF in DNA repair. XPF deficiency manifests in various diseases, including cancer, neurodegeneration, and aging-related disorders; it is also associated with conditions such as Xeroderma pigmentosum and fertility issues. By examining the molecular mechanisms and pathological consequences linked to XPF dysfunction, this study aims to elucidate the crucial role of XPF in genomic stability as a repair protein in BER and provide perspectives regarding its potential as a therapeutic target in related diseases.

Keywords: 5′-Gap pathway (5′ Gap LP-BER pathway); RECQ1; XPF (ERCC4); base excision repair (BER); nucleotide excision repair (NER).

Figure 1

DNA substrates before and after XPF cleavage. Created in https://BioRender.com (accessed on 30 November 2024).

Figure 2

A nucleotide excision repair (NER) pathway, simplified. The strand notation shown for the first step applies to all subsequent steps within the pathway. Unlabeled DNA ends are either polymerase extendable clean 3′-OH groups or 5′-PO₄ groups that can be ligated for the repair intermediates. (i) Global-genome NER (GG-NER). (ii) Transcription-coupled NER (TC-NER). Created through https://BioRender.com (accessed on 11 November 2024).

Figure 3

A base excision repair (BER) pathway, simplified. The strand notation shown for the first step applies to all subsequent steps within the pathway. Unlabeled DNA ends are either polymerase extendable clean 3′-OH groups or 5′-PO₄ groups that can be ligated for the repair intermediates. Created in https://BioRender.com (accessed on 11 November 2024).

Figure 4

A single-strand annealing (SSA) pathway, simplified. The strand notation shown for the first step applies to all subsequent steps within the pathway. Unlabeled DNA ends are either polymerase extendable clean 3′-OH groups or 5′-PO₄ groups that can be ligated for the repair intermediates. Created in https://BioRender.com (accessed on 11 November 2024).

Figure 5

A homologous recombination (HR) pathway, simplified. The strand notation shown for the first step applies to all subsequent steps within the pathway. Unlabeled DNA ends are either polymerase extendable clean 3′-OH groups or 5′-PO₄ groups that can be ligated for the repair intermediates. Created in https://BioRender.com (accessed on 11 November 2024).

Figure 6

Replication-independent repair (RIR) pathway, simplified. The strand notation shown for the first step applies to all subsequent steps within the pathway. Unlabeled DNA ends are either polymerase extendable clean 3′-OH groups or 5′-PO₄ groups that can be ligated for the repair intermediates. Created in https://BioRender.com (accessed on 11 November 2024).

Figure 7

A replication-dependent repair (RDR) pathway, simplified. The strand notation shown for the first step applies to all subsequent steps within the pathway. Unlabeled DNA ends are either polymerase extendable clean 3′-OH groups or 5′-PO₄ groups that can be ligated for the repair intermediates. Created in https://BioRender.com (accessed on 11 November 2024).

Figure 8

M1dG and εA structures. Created in https://BioRender.com (accessed on 11 November 2024).