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HMCES safeguards genome integrity and long-term self-renewal of hematopoietic stem cells during stress responses

ABSTRACT: HMCES safeguards genome integrity and long-term self-renewal of hematopoietic stem cells during stress responses

PROVIDER: PRJNA633383 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11804647_1.fastq.gz	Fastqsanger.gz
	SRR11804647_2.fastq.gz	Fastqsanger.gz
	SRR11804648_1.fastq.gz	Fastqsanger.gz
	SRR11804648_2.fastq.gz	Fastqsanger.gz
	SRR11804649_1.fastq.gz	Fastqsanger.gz

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HMCES safeguards genome integrity and long-term self-renewal of hematopoietic stem cells during stress responses

Project description:Hematopoietic stress drives quiescent hematopoietic stem cells (HSCs) to proliferate, generating reactive oxygen species and oxidative DNA damage including abasic sites. The coupling between abasic site generation and DNA replication during HSC stress responses, however, presents a challenge to accurately repair these abasic sites in the single-stranded DNA (ssDNA) generated during replication, leading to strand breaks and mutations. Here, we show in mice that HMCES, an evolutionarily conserved sensor and shield of ssDNA abasic sites, plays a pivotal role in overcoming this challenge. Hmces-deficient HSCs exhibited compromised long-term self-renewal capacity and elevated DNA damage in vivo in response to various hematopoietic stress, as well as broad attenuation of DNA damage response and repair pathways. Loss of HMCES also rendered HSCs hypersensitive to alcohol-derived acetaldehyde and might associate with increased susceptibility of leukemia. Collectively, our findings highlighted HMCES as a novel protector of HSCs and shed light on its physiological roles in regeneration and tumorigenesis.

2022-01-21 | GSE150721 | GEO

Nuclear exosome targeting complex safeguards hematopoietic stem cell self-renewal and genomic integrity through resolving R loops

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Genomic Integrity Safeguards Self-Renewal in Embryonic Stem Cells.

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Nuclear exosome targeting complex safeguards hematopoietic stem cell self-renewal and genomic integrity through resolving R loops

Project description:Pervasive transcription of the mammalian genome produces a vast repertoire of non-functional nascent transcripts, generating R loops and R-loop-induced DNA breaks. Such a coupling between continual transcription and a burst of R-loop formation, however, presents a challenge for hematopoietic stem cells (HSCs) to maintain their genome integrity. Here, we show that the nuclear exosome targeting (NEXT) complex, an RNA adaptor that targets non-functional nascent transcripts to the RNA exosome for decay, plays a pivotal role in overcoming this challenge. Hematopoietic-specific deletion of ZCCHC8, a core subunit of NEXT, not only leads to impaired HSC self-renewal but also causes elevated DNA lesions and upregulated DNA repair pathways in HSCs due to accumulated R loops. Moreover, dysregulation of ZCCHC8 occurs frequently in diffuse large B cell lymphoma (DLBCL) and is associated with poor clinical outcomes. Collectively, our findings highlight NEXT as a novel protector of HSCs and position it as a potential therapeutic target for DLBCL.

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