DNA Repair Defects and Other Mustakes in Drosophila melanogaster

Henderson, Daryl S.

doi:10.1006/meth.1999.0797

Cited by 16 publications

(8 citation statements)

References 199 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7E). (41,48). The recruitment of TopBP1 to stalled replication forks after inhibition of replication suggests that TopBP1 may be important in the rescue of stalled forks.…”

Section: Topbp1 In Dna Replication and Damage Responsementioning

confidence: 99%

BRCT Domain-containing Protein TopBP1 Functions in DNA Replication and Damage Response

Mäkiniemi¹,

Hillukkala²,

Tuusa³

et al. 2001

Journal of Biological Chemistry

192

219

View full text Add to dashboard Cite

Topoisomerase II␤-binding protein (TopBP1), a human protein with eight BRCT domains, is similar to Saccharomyces cerevisiae Dpb11 and Schizosaccharomyces pombe Cut5 checkpoint proteins and closely related to Drosophila Mus101. We show that human TopBP1 is required for DNA replication and that it interacts with DNA polymerase ⑀. In S phase TopBP1 colocalizes with Brca1 to foci that do not represent sites of ongoing DNA replication. Inhibition of DNA synthesis leads to relocalization of TopBP1 together with Brca1 to replication forks, suggesting a role in rescue of stalled forks. DNA damage induces formation of distinct TopBP1 foci that colocalize with Brca1 in S phase, but not in G 1 phase. We also show that TopBP1 interacts with the checkpoint protein hRad9. Thus, these results implicate TopBP1 in replication and checkpoint functions. DNA polymerases (pol)1 play essential roles in chromosomal DNA replication and repair. In Saccharomyces cerevisiae three essential nuclear polymerases, ␣, ␦, and ⑀ have important functions in DNA replication. S. cerevisiae pol ⑀ is isolated as a complex of a catalytic subunit and three smaller subunits, Dpb2, 3, and 4 (1). This four-subunit structure is also conserved in the human enzyme, which consists of a catalytic subunit (2), a B subunit (3, 4), and two smaller subunits (5). Pol ⑀ is a proofreading DNA polymerase, which has been implicated in DNA replication, as temperature-sensitive mutants show defects in DNA replication in both S. cerevisiae and Schizosaccharomyces pombe (6 -8). Moreover, pol ⑀ is associated with origins of DNA replication and it proceeds along the replication fork (9). In human cells, pol ⑀ is associated with actively replicated cellular DNA (10) and has been shown to perform an important fraction of replicative DNA synthesis (11). Surprisingly, the catalytic domain of pol ⑀ is not essential for viability in S. cerevisiae. Instead, the C terminus, which interacts with Dpb2, exerts all of the essential functions (12).Pol ⑀ has been proposed to function in the repair of UVdamaged DNA because it is able to catalyze UV-induced DNA synthesis in vivo (13) and performs efficient gap-filling synthesis in the reconstituted nucleotide excision repair system (14). A role in base excision repair is suggested by the fact that pol ⑀ mutants fail to support repair synthesis in vitro, and repair activity can be restored by the addition of purified pol ⑀ (15). Pol ⑀ has also been proposed to function in a specialized replication process required to repair double strand breaks (16). In addition to replicative and repair roles, it has been suggested that pol ⑀ coordinates transcriptional and cell cycle responses to DNA damage and replication blocks (17).In S. cerevisiae, a BRCT domain-containing protein, Dpb11, interacts with the pol ⑀ complex and was originally identified as a suppressor of pol ⑀ catalytic and Dpb2 subunit mutants (18,19). DPB11 is an essential gene required for DNA replication (18). The inability of DPB11 mutants to restrain mitosis in the presence of inco...

show abstract

“…7E). (41,48). The recruitment of TopBP1 to stalled replication forks after inhibition of replication suggests that TopBP1 may be important in the rescue of stalled forks.…”

Section: Topbp1 In Dna Replication and Damage Responsementioning

confidence: 99%

BRCT Domain-containing Protein TopBP1 Functions in DNA Replication and Damage Response

Mäkiniemi¹,

Hillukkala²,

Tuusa³

et al. 2001

Journal of Biological Chemistry

192

219

View full text Add to dashboard Cite

show abstract

“…More recently, using additional screens or by comparing Drosophila homologues with other species (Sibon et al, 1997(Sibon et al, , 1999Price et al, 2000;LaRocque et al, 2007;McVey et al, 2007;Wei and Rong, 2007;Klovstad et al, 2008), several other genes were identified that are implicated in proper cell cycle checkpoint function or DNA damage repair. Although discrepancies in survival pathways among different organisms do exist, it can be concluded that many genes involved in responses to DNA damage, and their pathways, are highly conserved (Henderson, 1999;Rhind and Russell, 2000;Sekelsky et al, 2000).Hydroxyurea (HU) is a compound that inhibits ribonucleoside dephosphate reductase and thereby blocks DNA synthesis (Hendricks and Mathews, 1998). This "classic" feature of HU has been widely used to induce intra-S and S/M checkpoints that delay progression through S phase and prevent mitotic entry due to the presence of incompletely replicated DNA.…”

mentioning

confidence: 99%

Stwl Modifies Chromatin Compaction and Is Required to Maintain DNA Integrity in the Presence of Perturbed DNA Replication

Vries

Siudeja

et al. 2009

MBoC

View full text Add to dashboard Cite

Hydroxyurea, a well-known DNA replication inhibitor, induces cell cycle arrest and intact checkpoint functions are required to survive DNA replication stress induced by this genotoxic agent. Perturbed DNA synthesis also results in elevated levels of DNA damage. It is unclear how organisms prevent accumulation of this type of DNA damage that coincides with hampered DNA synthesis. Here, we report the identification of stonewall (stwl) as a novel hydroxyureahypersensitive mutant. We demonstrate that Stwl is required to prevent accumulation of DNA damage induced by hydroxyurea; yet, Stwl is not involved in S/M checkpoint regulation. We show that Stwl is a heterochromatin-associated protein with transcription-repressing capacities. In stwl mutants, levels of trimethylated H3K27 and H3K9 (two hallmarks of silent chromatin) are decreased. Our data provide evidence for a Stwl-dependent epigenetic mechanism that is involved in the maintenance of the normal balance between euchromatin and heterochromatin and that is required to prevent accumulation of DNA damage in the presence of DNA replication stress. INTRODUCTIONCell cycle checkpoint pathways and DNA damage response pathways are essential mechanisms that control the order and timing of all cell cycle transitions and that ensure that critical events such as DNA replication and chromosome segregation are performed with high fidelity (Hartwell and Weinert, 1989;Elledge, 1996;Hurley and Bunz, 2007). In case these mechanisms fail, genetic abnormalities could be passed on to the following generations of cells, and this could lead to genomic instability and diseases such as cancer (Dasika et al., 1999;Houtgraaf et al., 2006). Cell cycle checkpoint and DNA repair genes have initially been identified using forward genetic screens in budding yeast (Saccharomyces cerevisiae) and fission yeast (Schizosaccharomyces pombe) (reviewed in O'Connell et al., 2000;Carr, 2002). Subsequently, forward genetic screens were also performed in Drosophila melanogaster and resulted in the identification of Ͼ30 mutagen-hypersensitive (mus) genes (Boyd et al., 1976(Boyd et al., , 1981Henderson et al., 1987). Several of these mus genes have been cloned, and their function has been assigned to checkpoint regulation or DNA damage repair (Harris et al., 1996;Oshige et al., 1999;Brodsky et al., 2000;Yamamoto et al., 2000). More recently, using additional screens or by comparing Drosophila homologues with other species (Sibon et al., 1997(Sibon et al., , 1999Price et al., 2000;LaRocque et al., 2007;McVey et al., 2007;Wei and Rong, 2007;Klovstad et al., 2008), several other genes were identified that are implicated in proper cell cycle checkpoint function or DNA damage repair. Although discrepancies in survival pathways among different organisms do exist, it can be concluded that many genes involved in responses to DNA damage, and their pathways, are highly conserved (Henderson, 1999;Rhind and Russell, 2000;Sekelsky et al., 2000).Hydroxyurea (HU) is a compound that inhibits ribonucleoside dephosphate redu...

show abstract

“…These defects are germline autonomous. In fact, complete or almost complete maternal-effect lethality is a characteristic feature of females that are homozygous for mutant alleles of the genes engaged in the G2/M transition control (Henderson 1999). For example, only $20% of embryos hatch from eggs of females that are both homozygous for the strong mnk mutant alleles and lack Chk2 function (Xu et al 2001;Masrouha et al 2003;Takada et al 2003;Xu and Du 2003;Brodsky et al 2004).…”

Section: Discussionmentioning

confidence: 99%

HorkaD, a Chromosome Instability-Causing Mutation in Drosophila, Is a Dominant-Negative Allele of lodestar

et al. 2009

View full text Add to dashboard Cite

Correct segregation of chromosomes is particularly challenging during the rapid nuclear divisions of early embryogenesis. This process is disrupted by Horka D , a dominant-negative mutation in Drosophila melanogaster that causes female sterility due to chromosome tangling and nondisjunction during oogenesis and early embryogenesis. Horka D also renders chromosomes unstable during spermatogenesis, which leads to the formation of diplo//haplo mosaics, including the gynandromorphs. Complete loss of gene function brings about maternal-effect lethality: embryos of the females without the Horka D -identified gene perish due to disrupted centrosome function, defective spindle assembly, formation of chromatin bridges, and abnormal chromosome segregation during the cleavage divisions. These defects are indicators of mitotic catastrophe and suggest that the gene product acts during the meiotic and the cleavage divisions, an idea that is supported by the observation that germ-line chimeras exhibit excessive germ-line and cleavage function. The gene affected by the Horka D mutation is lodestar, a member of the helicase-related genes. The Horka D mutation results in replacement of Ala777 with Thr, which we suggest causes chromosome instability by increasing the affinity of Lodestar for chromatin.

show abstract

DNA Repair Defects and Other Mustakes in Drosophila melanogaster

Cited by 16 publications

References 199 publications

BRCT Domain-containing Protein TopBP1 Functions in DNA Replication and Damage Response

BRCT Domain-containing Protein TopBP1 Functions in DNA Replication and Damage Response

Stwl Modifies Chromatin Compaction and Is Required to Maintain DNA Integrity in the Presence of Perturbed DNA Replication

HorkaD, a Chromosome Instability-Causing Mutation in Drosophila, Is a Dominant-Negative Allele of lodestar

Contact Info

Product

Resources

About