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Horizontal acquisition of a DNA ligase improves DNA damage tolerance in eukaryotes

ABSTRACT: Bdelloid rotifers are part of the restricted circle of multicellular animals that can withstand a wide range of genotoxic stresses at any stage of their life cycle. In this study, bdelloid rotifer Adineta vaga was used as a model to decipher the molecular basis of their extreme tolerance. Proteomic analysis showed that a specific DNA ligase, different from those usually involved in DNA repair in eukaryotes, is strongly over-represented upon ionizing radiation. A phylogenetic analysis revealed its orthology to prokaryotic DNA ligase E, and its horizontal acquisition by bdelloid rotifers and plausibly other eukaryotes. The fungus Mortierella verticillata, having a single copy of this DNA Ligase E homolog, also exhibits an increased radiation tolerance with an over-expression of this DNA ligase E following X-ray exposure. We also provide evidence that A. vaga ligase E is a major contributor of DNA breaks ligation activity, which is a common step of all important DNA repair pathways. Consistently, its heterologous expression in human cell lines significantly improved their radio-tolerance. Overall, this study highlights the potential of horizontal gene transfers in eukaryotes, and their contribution to the adaptation to extreme conditions.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Adineta Vaga

SUBMITTER: Marc Dieu

LAB HEAD: Karine Van

PROVIDER: PXD043051 | Pride | 2024-01-24

REPOSITORIES: Pride

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Project description:A major challenge in bone allogeneic marrow (BM) transplantation is overcoming engraftment resistance to avoid the clinical problem of graft rejection. Identifying genes and pathways that regulate BM engraftment may reveal molecular targets for overcoming these engraftment barriers. Previously, we developed a mouse model of BM transplantation that utilizes recipient conditioning with non-myeloablative total body irradiation followed by transplantation of allogeneic BM cells. We defined TBI doses that lead to graft rejection, that are permissive for engraftment, and mouse strain variation with regards to the permissive TBI dose. We now report gene expression analysis, using the Agilent Mouse 8x60K v3 expression arrays, in spleen of mice conditioned with TBI doses for evaluation in correlation to the expected engraftment phenotype. The spleens of mice given TBI demonstrated extensive differential gene expression, compared with un-irradiated controls, at both multiple testing-corrected P < .05 and fold change greater than or equal to 2 levels. Functional analysis revealed significant enrichment for up-regulation of canonical pathways involved in inflammation, even when treated with TBI doses not permissive for engraftment. Consistent with this the most significantly associated upstream regulators included lipopolysaccharide, tumor necrosis factor, and a toll-like receptor. Unique to engrafting mice, however, were enrichment for a down-regulated canonical pathway related to B-cell development. Results from this analysis have identified canonical pathways and upstream regulators of BM engraftment in mice and may lead to new approaches to overcome the problem of graft rejection complicating clinical BM transplantation. Each individual sample was pooled from 3 mice and performed in triplicate for each experimental group (TBI 300 cGy, 400 cGy, or 500 cGy) and for each strain mice (BALB.K or B10.BR) for statistical analysis. Additional arrays were perfromed for TBI 800 cGy (BALB.K) and TBI 900 cGy (B10.BR) for anlaysis of gene expressive after myeloablative condition.

			Action	DRS
	1000Gy-peptides_1_1_0.mzid.gz	Mzid
	800Gy-peptides_1_1_0.mzid.gz	Mzid
	TableS1.xlsx	Xlsx
	TableS2.xlsx	Xlsx
	TableS3.xlsx	Xlsx

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Horizontal acquisition of a DNA ligase improves DNA damage tolerance in eukaryotes

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