DNA Double-Strand Breaks: A Double-Edged Sword for Trypanosomatids

Abstract

For nearly all eukaryotic cells, stochastic DNA double-strand breaks (DSBs) are one of the most deleterious types of DNA lesions. DSB processing and repair can cause sequence deletions, loss of heterozygosity, and chromosome rearrangements resulting in cell death or carcinogenesis. However, trypanosomatids (single-celled eukaryotes parasites) do not seem to follow this premise strictly. Several studies have shown that trypanosomatids depend on DSBs to perform several events of paramount importance during their life cycle. For Trypanosoma brucei, DSBs formation is associated with host immune evasion via antigenic variation. In Trypanosoma cruzi, DSBs play a crucial role in the genetic exchange, a mechanism that is still little explored but appear to be of fundamental importance for generating variability. In Leishmania spp., DSBs are necessary to generate genomic changes by gene copy number variation (CNVs), events that are essential for these organisms to overcome inhospitable conditions. As DSB repair in trypanosomatids is primarily conducted via homologous recombination (HR), most of the events associated with DSBs are HR-dependent. This review will discuss the latest findings on how trypanosomatids balance the benefits and inexorable challenges caused by DSBs.

p53 Isoforms as Cancer Biomarkers and Therapeutic Targets

“…DNA DSBs are one of the most harmful types of DNA damage [100]. Correct DNA DSB repair is important for prohibiting tumorigenesis [100].…”

“…DNA DSBs are one of the most harmful types of DNA damage [100]. Correct DNA DSB repair is important for prohibiting tumorigenesis [100]. It is known that p53 is activated in response to DNA damage [101], which, in turn, inhibits DNA DSB repair [102] by downregulating DNA DSB repair genes including RAD51, RAD52, LIG4, WRN, and XRCC4 [103].…”

Impact of Genetic Diversity and Genome Plasticity of Leishmania spp. in Treatment and the Search for Novel Chemotherapeutic Targets

“…These extrachromosomal gene copies are commonly found in Leishmania under stress, but are also found in wild-type populations ( Ouellette and Borst, 1991 ; Grondin et al., 1993 ; Leprohon et al., 2009 ). It has been reported that there are pairs of repeated sequences surrounding sets of genes in Leishmania ( Leprohon et al., 2009 ; Ubeda et al., 2014 ; Bussotti et al., 2018 ; Carnielli et al., 2018 ) and DNA double-strand breaks near or within these repeated sequences may induce homologous recombination, which is associated with an increase in gene rearrangements ( Genois et al., 2014 ; da Silva, 2021 ).…”

Experimental Hybridization in Leishmania: Tools for the Study of Genetic Exchange

“…We speculate that ROS levels in the digested blood meal below a threshold level that is lethal for the parasites or sand fly [ 45 ] may be able to trigger repairable DNA damage and genetic exchange. Alternatively, spontaneous DNA breaks are often associated with replicative stress [ 46 ]. In the first two days post-blood meal, the sand fly midgut contains proliferating promastigotes marked by DSBs catalyzed during the S phase.…”

“…The major repair mechanism of DNA double-strand breaks (DSB) involves the non-homologous end joining (NHEJ) pathway, which ligates the ends of the break in order to fully restore it. It is widely accepted that trypanosomatids lack a canonical NHEJ and that homologous recombination (HR) is instead the most important DSB repair pathway, although the mechanisms remain unclear (see review in [ 46 ]). The drastic increase in in vitro hybridization post-irradiation suggests an interplay between the DNA break repair machinery and meiosis in these parasites, ultimately leading to upregulation of genes involved in the fusion of gametes and nuclei.…”