Bloom syndrome helicase contributes to germ line development and longevity in zebrafish

Abstract

RecQ helicases—also known as the “guardians of the genome”—play crucial roles in genome integrity maintenance through their involvement in various DNA metabolic pathways. Aside from being conserved from bacteria to vertebrates, their importance is also reflected in the fact that in humans impaired function of multiple RecQ helicase orthologs are known to cause severe sets of problems, including Bloom, Werner, or Rothmund-Thomson syndromes. Our aim was to create and characterize a zebrafish (Danio rerio) disease model for Bloom syndrome, a recessive autosomal disorder. In humans, this syndrome is characterized by short stature, skin rashes, reduced fertility, increased risk of carcinogenesis, and shortened life expectancy brought on by genomic instability. We show that zebrafish blm mutants recapitulate major hallmarks of the human disease, such as shortened lifespan and reduced fertility. Moreover, similarly to other factors involved in DNA repair, some functions of zebrafish Blm bear additional importance in germ line development, and consequently in sex differentiation. Unlike fanc genes and rad51, however, blm appears to affect its function independent of tp53. Therefore, our model will be a valuable tool for further understanding the developmental and molecular attributes of this rare disease, along with providing novel insights into the role of genome maintenance proteins in somatic DNA repair and fertility.

Unraveling DNA Repair Processes In Vivo: Insights from Zebrafish Studies

“…This observation implied that rag1 might play a potential role in maintaining genomic integrity to regulate and prevent premature aging. Furthermore, mutations in the genes atm and blm, which were previously discussed in the context of cancer and germ cell development, also result in decreased lifespans, suggesting that these genes may have multiple functions in the lifespan regulation of living organisms [76,84]. All these studies collectively emphasize the pivotal role of DNA repair mechanisms in aging, illustrating how genomic integrity is closely intertwined with organismal longevity.…”

“…A depletion of blm in zebrafish leads to a bias towards male phenotypes with reduced fertility. In the testes of blm mutants, spermatocytes are arrested in meiotic phase I, suggesting that infertility in blm mutants is caused by meiotic arrest of spermatocytes [84]. Taken together, these observations highlight the crucial role of the FA/HR pathway in repairing DNA cross-link for proper germ cell development.…”

HELQ deficiency impairs the induction of primordial germ cell‐like cells

“…Previous studies have demonstrated that disruption of the DNA damage repair mechanisms promote genomic instability, and lead to increased risks for cancer susceptibility and germline defects across species, such as fly, zebrafish, mouse and human [ 44 , 45 , 46 , 47 ]. For example, the FA pathway is a dominant mechanism for inter‐strand cross‐link repair in vertebrates.…”

“…BLM gene encodes a 3′‐5′ DNA helicase, which is required for precise double‐stranded DNA break repair, processing of DNA replication intermediates and rDNA metabolism. Impaired function of BLM caused shortened lifespan and reduced fertility in zebrafish, mouse and human [ 46 , 51 ]. HELQ is also a crucial DNA helicase for maintaining genomic stability, which acts through a mechanism distinct from the function of FA pathway [ 29 , 52 ].…”

Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process

“…Here we found 28 factors that may represent perhaps the most important proteins that could mediate the age-controlling aspects of GPR19 biology. These proteins included multiple factors shown to exert a strong regulatory role in the aging process, e.g., DNA damage repair factors BLM [ 207 ], XRCC5 [ 208 ], RECQL4 [ 209 ], FAAP100 [ 210 ], FOXM1 [ 211 ], NUCKS1 [ 212 ], FEN1 [ 213 ]; energy metabolism factors UCP2 [ 214 ], PARP1 [ 215 ], HMOX1 [ 216 ], ARG2 [ 217 ], IDE [ 218 ]; cell cycle/fate control factors CDKN1A [ 219 ], CDK5 [ 220 ], WWC1 [ 221 ], CENPW [ 222 ]; transport and proteostasis regulation factors ZMPSTE24 [ 223 ], HSPA9, also known as Mortalin [ 224 ], SQSTM1 [ 225 ], PPM1L [ 226 ], PICALM [ 227 ]. To assess the degree of specificity of this cohort of GPR19-Aging-associated factors, we tested multiple (n = 10) random datasets the same numerical size as the unbiased aging dataset to assess the potential for random intersections between the GPR19-associated dataset with one the same size as the aging-specific dataset.…”