DNA damage checkpoint and repair: From the budding yeast Saccharomyces cerevisiae to the pathogenic fungus Candida albicans

Abstract

Cells are constantly challenged by internal or external genotoxic assaults, which may induce a high frequency of DNA lesions, leading to genome instability. Accumulation of damaged DNA is severe or even lethal to cells and can result in abnormal proliferation that can cause cancer in multicellular organisms, aging or cell death. Eukaryotic cells have evolved a comprehensive defence system termed the DNA damage response (DDR) to monitor and remove lesions in their DNA. The DDR has been extensively studied in the budding yeast Saccharomyces cerevisiae. Emerging evidence indicates that DDR genes in the pathogenic fungus Candida albicans show functional consistency with their orthologs in S. cerevisiae, but may act through distinct mechanisms. In particular, the DDR in C. albicans appears critical for resisting DNA damage stress induced by reactive oxygen species (ROS) produced from immune cells, and this plays a vital role in pathogenicity. Therefore, DDR genes could be considered as potential targets for clinical therapies. This review summarizes the identified DNA damage checkpoint and repair genes in C. albicans based on their orthologs in S. cerevisiae, and discusses their contribution to pathogenicity in C. albicans.

Keywords: Candida albicans; DNA damage checkpoint; DNA damage repair; DNA damage response; Pathogenicity.

Fig. 1

Schematic diagram of DNA damage response. External and internal stresses induce DNA lesions. The damaged DNA may activate the DNA damage response signaling pathway, where DNA damage checkpoints play a central role in arresting the cell cycle and mediating the DNA repair process. The unsuccessful repairing of DNA lesions may cause apoptosis, cell death or cancer. Homologous recombination (HR); Non-homologous end joining (NHEJ); Base excision repair (BER); Nucleotide excision repair (NER); Postreplication repair (PRR); Mismatch repair (MMR).

Fig. 2

Phosphatases involved in the dephosphorylation of checkpoint kinase Rad53. (A) In S. cerevisiae, ScPsy2 and ScPtc2 are required for the dephosphorylation of ScRad53; ScPsy2 interacts with the kinase domain (KD) and ScPtc2 interacts with the FHA (N terminus) domain. In C. albicans, Psy2 interacts with the FHA (C terminus) domain, but Ptc2 shows no clear interaction with Rad53. (B) Pph3 and Psy2 form a complex and play a dominant role in the dephosphorylation of Rad53 in C. albicans. Psy4 and Tip41 act as adaptors for Pph3 and Psy2. In particular, Tip41 plays an important role in the dephosphorylation of Rad53 during the recovery from DNA damage stress, while Psy4 seems dispensable for the dephosphorylation of Rad53. Unlike the pattern in S. cerevisiae, the Pph3-Psy2-Psy4 complex is not involved in the dephosphorylation of H2A. Additionally, Glc7 regulates the dephosphorylation of Rad53 both in S. cerevisiae and C. albicans, but the direct interaction between Rad53 and Glc7 is unclear. Moreover, Glc7 is involved in the dephosphorylation of γH2A in S. cerevisiae, but the role in C. albicans remains to be established. The red question mark means uncovered interaction according to current data. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

DNA damage response genes that are responsible for the pathogenicity of C. albicans cells. Typical genes involved in different DDR pathways are selected. RAD52, LIG4, RTT109, RFX2, RAD23 and TOP2 play positive roles in pathogenicity. TOP1, PPH3, PSY2 and PSY4 play negative roles in pathogenicity. SDS22 overexpression attenuates pathogenicity.