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 .

Transcriptional Profiling of the Candida albicans Response to the DNA Damage Agent Methyl Methanesulfonate

“…As well, histone acetyltransferase RTT109 was upregulated; its ortholog in S. cerevisiae functions in the NHEJ pathway through interaction with ScVps75 [ 35 ]. DNA helicases have major roles in genome maintenance by unwinding structured nucleic acids and thus are involved in HR, NER, and PPR pathways [ 4 , 36 ]. Here, a putative 3’-5’ DNA helicase MPH1 was induced with MMS treatment in C. albicans .…”

“…However, several intrinsic and extrinsic factors, including cell metabolism, replication stress, radiation, and viral infection, may stress genomic DNA, introducing a variety of DNA lesions [ 2 , 3 ]. In particular, reactive oxygen species (ROS) and other active molecules generated by host immune cells cause oxidative DNA damage stress on pathogenic microorganisms [ 4 , 5 ]. To defend against such damage-inducing events, DNA damage response (DDR) pathways are employed for cells to sense and fix damaged DNA, allowing successful colonization in hosts [ 6 , 7 , 8 ].…”

“…The sensor kinase Mec1 mediates a classical checkpoint activation pathway, where its activation phosphorylates, with the participation of adaptors Rad9 or Mrc1, the downstream effector kinase Rad53. The activated Rad53 further regulates the transcription of DNA damage response genes and dNTP pools directly or in a Dun1-dependent manner [ 4 ]. Subsequently, various DNA damage repair systems, including homologous recombination (HR), non-homologous end-joining (NHEJ), base excision repair (BER), nucleotide excision repair (NER), DNA postreplication repair (PRR), or DNA mismatch repair (MMR), are recruited to various DNA lesions to repair damaged DNA [ 9 ].…”

“…In the pathogenic yeast Candida albicans , several DNA damage response genes have been identified that show similar roles to their orthologs in S. cerevisiae [ 4 ]. Moreover, DNA damage repair-related genes also contribute to the pathogenicity of C. albicans cells.…”

“…The sensor kinase Mec1 mediates a classical checkpoint activation pathway, where its activation phosphorylates, with the participation of adaptors Rad9 or Mrc1, the downstream effector kinase Rad53. The activated Rad53 In the pathogenic yeast Candida albicans, several DNA damage response genes have been identified that show similar roles to their orthologs in S. cerevisiae [4]. Moreover, DNA damage repair-related genes also contribute to the pathogenicity of C. albicans cells.…”