RecQ5 in mammalian cells has been suggested to suppress inappropriate homologous recombination.However,the specific pathway(s)in which it is involved and the underlining mechanism(s)remain poorly understood.We took ad...RecQ5 in mammalian cells has been suggested to suppress inappropriate homologous recombination.However,the specific pathway(s)in which it is involved and the underlining mechanism(s)remain poorly understood.We took advantage of genetic tools in Drosophila to investigate how Drosophila RecQ5(dRecQ5)functions in vivo in homologous recombination-mediated double strand break(DSB)repair.We generated null alleles of dRecQ5 using the targeted recombination technique.The mutant animals are homozygous viable,but with growth retardation during development.The mutants are sensitive to both exogenous DSB-inducing treatment,such as gamma-irradiation,and endogenously induced double strand breaks(DSBs)by I-Sce I endonuclease.In the absence of dRecQ5,single strand annealing(SSA)-mediated DSB repair is compromised with compensatory increases in either inter-homologous gene conversion,or non-homologous end joining(NHEJ)when inter-chromosomal homologous sequence is unavailable.Loss of function of dRecQ5 also leads to genome instability in loss of heterozygosity(LOH)assays.Together,our data demonstrate that dRecQ5 functions in SSA-mediated DSB repair to achieve its full efficiency and in suppression of LOH in Drosophila.展开更多
The clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP)ribose polymerase(PARP)inhibitors.However,the efficacy of these compounds is hampered by resistance,which is attrib...The clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP)ribose polymerase(PARP)inhibitors.However,the efficacy of these compounds is hampered by resistance,which is attributed to numerous mechanisms including rewiring of the DNA damage response to favour pathways that repair PARP inhibitor-mediated damage.Here,we comment on recent findings by our group identifying the lysine methyltransferase SETD1A as a novel factor that conveys PARPi resistance.We discuss the implications,with a particular focus on epigenetic modifications and H3K4 methylation.We also deliberate on the mechanisms responsible,the consequences for the refinement of PARP inhibitor use in the clinic,and future possibilities to circumvent drug resistance in DNA-repair deficient cancers.展开更多
基金This work has been financially supported by the National Basic Research Program(973 Program)(Nos.2009CB918702,2005CB522804)the National Natural Science Foundation of China(Grant Nos.30623005,90608029 and 30771217)Chinese Academy of Sciences(KSCX1-YW-R-70).
文摘RecQ5 in mammalian cells has been suggested to suppress inappropriate homologous recombination.However,the specific pathway(s)in which it is involved and the underlining mechanism(s)remain poorly understood.We took advantage of genetic tools in Drosophila to investigate how Drosophila RecQ5(dRecQ5)functions in vivo in homologous recombination-mediated double strand break(DSB)repair.We generated null alleles of dRecQ5 using the targeted recombination technique.The mutant animals are homozygous viable,but with growth retardation during development.The mutants are sensitive to both exogenous DSB-inducing treatment,such as gamma-irradiation,and endogenously induced double strand breaks(DSBs)by I-Sce I endonuclease.In the absence of dRecQ5,single strand annealing(SSA)-mediated DSB repair is compromised with compensatory increases in either inter-homologous gene conversion,or non-homologous end joining(NHEJ)when inter-chromosomal homologous sequence is unavailable.Loss of function of dRecQ5 also leads to genome instability in loss of heterozygosity(LOH)assays.Together,our data demonstrate that dRecQ5 functions in SSA-mediated DSB repair to achieve its full efficiency and in suppression of LOH in Drosophila.
基金supported by a PhD studentship from the University of Birmingham and Cancer Research UK(C17422/A25154)awarded to Sweatman E and Higgs MRa Breast Cancer Now project grant(2019AugPR1320)supporting Bayley R(awarded to Garcia P)an MRC Career Development Fellowship(MR/P009085/1)awarded to Higgs MR.
文摘The clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP)ribose polymerase(PARP)inhibitors.However,the efficacy of these compounds is hampered by resistance,which is attributed to numerous mechanisms including rewiring of the DNA damage response to favour pathways that repair PARP inhibitor-mediated damage.Here,we comment on recent findings by our group identifying the lysine methyltransferase SETD1A as a novel factor that conveys PARPi resistance.We discuss the implications,with a particular focus on epigenetic modifications and H3K4 methylation.We also deliberate on the mechanisms responsible,the consequences for the refinement of PARP inhibitor use in the clinic,and future possibilities to circumvent drug resistance in DNA-repair deficient cancers.
