The Knowns Unknowns: Exploring the Homologous Recombination Repair Pathway in Toxoplasma gondii

Abstract

Toxoplasma gondii is an apicomplexan parasite of medical and veterinary importance which causes toxoplasmosis in humans. Great effort is currently being devoted toward the identification of novel drugs capable of targeting such illness. In this context, we believe that the thorough understanding of the life cycle of this model parasite will facilitate the identification of new druggable targets in T. gondii. It is important to exploit the available knowledge of pathways which could modulate the sensitivity of the parasite to DNA damaging agents. The homologous recombination repair (HRR) pathway may be of particular interest in this regard as its inactivation sensitizes other cellular models such as human cancer to targeted therapy. Herein we discuss the information available on T. gondii's HRR pathway from the perspective of its conservation with respect to yeast and humans. Special attention was devoted to BRCT domain-containing and end-resection associated proteins in T. gondii as in other experimental models such proteins have crucial roles in early/late steps or HRR and in the pathway choice for double strand break resolution. We conclude that T. gondii HRR pathway is a source of several lines of investigation that allow to to comprehend the extent of diversification of HRR in T. gondii. Such an effort will serve to determine if HRR could represent a potential targer for the treatment of toxoplasmosis.

Apicomplexa and Histone Variants: What’s New?

“…DSB can be repaired by two main mechanisms: nonhomologous end joining (NHEJ) and homologous recombination repair (HRR); the first is an error-prone mechanism available along the cell cycle, and the second is an error-free mechanism active at S/G2 phases of cell cycle because of the requirement of sister chromatid as template [131][132][133][134]. Both mechanisms were described in T. gondii [14,135], but Plasmodium genus is thought to rely only on HRR [136][137][138].…”

“…ATM is able to phosphorylate H2A.X at SQE motif as well as other DSB repair enzymes allowing the spreading of γH2A.X and a correct DNA damage response (DDR) at DSB site ( Figure 4A). ATM kinase is present in T. gondii and P. falciparum [14]. In T. gondii, the MYST family lysine acetyltransferase TgMYST-B has shown to mediate DDR induced by methyl methanesulfonate (MMS) and to stimulate the ATM expression at gene level [140].…”

“…control was proposed as a key element to facilitate parasite gene expression, DNA replication, and DNA repair [13][14][15].…”

Anticorpos presentes em amostras de líquido amniótico de pacientes com alto risco de toxoplasmose congênita reconhecem diferentes marcadores antigênicos de diferentes extratos proteicos de Toxoplasma gondii

“…A fase aguda é caracterizada pela alta parasitemia da forma taquizoíto do parasito. Em seguida, na fase crônica, a parasitemia entra em latência e os parasitos invadem as células se multiplicando na forma de bradizoítos dentro de cistos teciduais que podem permanecer viáveis durante toda a vida do hospedeiro (FENOY et al, 2016;MOSE et al, 2017). Durante a infecção, o parasito é capaz de penetrar nas células migratórias do sistema imune, como monócitos, linfócitos e células dendríticas, sendo disseminado pelo organismo e alcançando outros tecidos (LAMBERT et al, 2006;MOSE et al, 2017;SIBLEY et al, 2011).…”

“…Durante a infecção, o parasito é capaz de penetrar nas células migratórias do sistema imune, como monócitos, linfócitos e células dendríticas, sendo disseminado pelo organismo e alcançando outros tecidos (LAMBERT et al, 2006;MOSE et al, 2017;SIBLEY et al, 2011). No cérebro, região de imunoprivilégio, as complicações compreendem disfunções neurológicas, encefalites e coriorretinites (FENOY et al, 2016;GASHOUT et al, 2016;MOSE et al, 2017;ASSOLINI et al, 2017;FUGLEWICZ; PIOTROWSKI; STODOLAK, 2017).…”