Lisa A. Moreau
Harvard University
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Lisa A. Moreau.
Science | 2007
Bijan Sobhian; Genze Shao; Dana R. Lilli; Aedín C. Culhane; Lisa A. Moreau; Bing Xia; David M. Livingston; Roger A. Greenberg
Mutations affecting the BRCT domains of the breast cancer–associated tumor suppressor BRCA1 disrupt the recruitment of this protein to DNA double-strand breaks (DSBs). The molecular structures at DSBs recognized by BRCA1 are presently unknown. We report the interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein. RAP80 targets a complex containing the BRCA1-BARD1 (BRCA1-associated ring domain protein 1) E3 ligase and the deubiquitinating enzyme (DUB) BRCC36 to MDC1-γH2AX–dependent lysine6- and lysine63-linked ubiquitin polymers at DSBs. These events are required for cell cycle checkpoint and repair responses to ionizing radiation, implicating ubiquitin chain recognition and turnover in the BRCA1-mediated repair of DSBs.
Blood | 2009
Alejandro Gutierrez; Takaomi Sanda; Ruta Grebliunaite; Arkaitz Carracedo; Leonardo Salmena; Yebin Ahn; Suzanne E. Dahlberg; Donna Neuberg; Lisa A. Moreau; Stuart S. Winter; Richard S. Larson; Jianhua Zhang; Alexei Protopopov; Lynda Chin; Pier Paolo Pandolfi; Lewis B. Silverman; Stephen P. Hunger; Stephen E. Sallan; A. Thomas Look
To more comprehensively assess the pathogenic contribution of the PTEN-PI3K-AKT pathway to T-cell acute lymphoblastic leukemia (T-ALL), we examined diagnostic DNA samples from children with T-ALL using array comparative genomic hybridization and sequence analysis. Alterations of PTEN, PI3K, or AKT were identified in 47.7% of 44 cases. There was a striking clustering of PTEN mutations in exon 7 in 12 cases, all of which were predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed to induce remission in 3 of the 4 patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, compared with none of the 12 patients with mutations of PTEN exon 7 (P = .007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings add significant support to the rationale for the development of therapies targeting the PTEN-PI3K-AKT pathway in T-ALL.
Nature Cell Biology | 2009
Yingli Sun; Xiaofeng Jiang; Ye Xu; Marina K. Ayrapetov; Lisa A. Moreau; Johnathan R. Whetstine; Brendan D. Price
DNA double-strand break (DSB) repair involves complex interactions between chromatin and repair proteins, including Tip60, a tumour suppressor. Tip60 is an acetyltransferase that acetylates both histones and ATM (ataxia telangiectasia mutated) kinase. Inactivation of Tip60 leads to defective DNA repair and increased cancer risk. However, how DNA damage activates the acetyltransferase activity of Tip60 is not known. Here, we show that direct interaction between the chromodomain of Tip60 and histone H3 trimethylated on lysine 9 (H3K9me3) at DSBs activates the acetyltransferase activity of Tip60. Depletion of intracellular H3K9me3 blocks activation of the acetyltransferase activity of Tip60, resulting in defective ATM activation and widespread defects in DSB repair. In addition, the ability of Tip60 to access H3K9me3 is dependent on the DNA damage-induced displacement of HP1β (heterochromatin protein 1β) from H3K9me3. Finally, we demonstrate that the Mre11–Rad50–Nbs1 (MRN) complex targets Tip60 to H3K9me3, and is required to activate the acetyltransferase activity of Tip60. These results reveal a new function for H3K9me3 in coordinating activation of Tip60-dependent DNA repair pathways, and imply that aberrant patterns of histone methylation may contribute to cancer by altering the efficiency of DSB repair.
Nature Cell Biology | 2002
Koji Nakanishi; Toshiyasu Taniguchi; Velvizhi Ranganathan; Helen V. New; Lisa A. Moreau; Maria Stotsky; Christopher G. Mathew; Michael B. Kastan; David T. Weaver; Alan D. D'Andrea
Fanconi anaemia (FA) and Nijmegen breakage syndrome (NBS) are autosomal recessive chromosome instability syndromes with distinct clinical phenotypes. Cells from individuals affected with FA are hypersensitive to mitomycin C (MMC), and cells from those with NBS are hypersensitive to ionizing radiation. Here we report that both NBS cell lines and individuals with NBS are hypersensitive to MMC, indicating that there may be functional linkage between FA and NBS. In wild-type cells, MMC activates the colocalization of the FA subtype D2 protein (FANCD2) and NBS1 protein in subnuclear foci. Ionizing radiation activates the ataxia telangiectasia kinase (ATM)-dependent and NBS1-dependent phosphorylation of FANCD2, resulting in an S-phase checkpoint. NBS1 and FANCD2 therefore cooperate in two distinct cellular functions, one involved in the DNA crosslink response and one involved in the S-phase checkpoint response.
Nature Structural & Molecular Biology | 2009
Ashish Lal; Yunfeng Pan; Francisco Navarro; Derek M. Dykxhoorn; Lisa A. Moreau; Eti Meire; Zvi Bentwich; Judy Lieberman; Dipanjan Chowdhury
Terminally differentiated cells have a reduced capacity to repair double-stranded breaks, but the molecular mechanism behind this downregulation is unclear. Here we find that miR-24 is upregulated during postmitotic differentiation of hematopoietic cell lines and regulates the histone variant H2AX, a protein that has a key role in the double-stranded break response. We show that the H2AX 3′ untranslated region contains conserved miR-24 binding sites that are indeed regulated by miR-24. During terminal differentiation, both H2AX mRNA and protein levels are substantially reduced by miR-24 upregulation in in vitro differentiated cells; similar diminished levels are found in primary human blood cells. miR-24–mediated suppression of H2AX renders cells hypersensitive to γ-irradiation and genotoxic drugs, a phenotype that is fully rescued by overexpression of miR-24–insensitive H2AX. Therefore, miR-24 upregulation in postreplicative cells reduces H2AX and makes them vulnerable to DNA damage.
Nature Medicine | 2011
Neil Johnson; Yu-Chen Li; Zandra E. Walton; Katherine A. Cheng; Danan Li; Scott J. Rodig; Lisa A. Moreau; Christine Unitt; Roderick T. Bronson; Huw D. Thomas; David R. Newell; Alan D. D'Andrea; Nicola J. Curtin; Kwok-Kin Wong; Geoffrey I. Shapiro
Cells that are deficient in homologous recombination, such as those that lack functional breast cancer–associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclin-dependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA–wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers.
Journal of Clinical Investigation | 2007
Richard D. Kennedy; Clark C. Chen; Patricia Stuckert; Elyse M. Archila; Michelle de la Vega; Lisa A. Moreau; Akiko Shimamura; Alan D. D’Andrea
The Fanconi anemia (FA) pathway maintains genomic stability in replicating cells. Some sporadic breast, ovarian, pancreatic, and hematological tumors are deficient in FA pathway function, resulting in sensitivity to DNA-damaging agents. FA pathway dysfunction in these tumors may result in hyperdependence on alternative DNA repair pathways that could be targeted as a treatment strategy. We used a high-throughput siRNA screening approach that identified ataxia telangiectasia mutated (ATM) as a critical kinase for FA pathway-deficient human fibroblasts. Human fibroblasts and murine embryonic fibroblasts deficient for the FA pathway were observed to have constitutive ATM activation and Fancg(-/-)Atm(-/-) mice were found to be nonviable. Abrogation of ATM function in FA pathway-deficient cells resulted in DNA breakage, cell cycle arrest, and apoptotic cell death. Moreover, Fanconi anemia complementation group G- (FANCG-) and FANCC-deficient pancreatic tumor lines were more sensitive to the ATM inhibitor KU-55933 than isogenic corrected lines. These data suggest that ATM and FA genes function in parallel and compensatory roles to maintain genomic integrity and cell viability. Pharmaceutical inhibition of ATM may have a role in the treatment of FA pathway-deficient human cancers.
Cancer Cell | 2012
Teeara Berry; William Luther; Namrata Bhatnagar; Yann Jamin; Evon Poon; Takaomi Sanda; De-Sheng Pei; Bandana Sharma; Winston R. Vetharoy; Albert Hallsworth; Zai Ahmad; Karen Barker; Lisa A. Moreau; Hannah Webber; Wenchao Wang; Qingsong Liu; Antonio R. Perez-Atayde; Scott J. Rodig; Nai-Kong Cheung; Florence I. Raynaud; Bengt Hallberg; Simon P. Robinson; Nathanael S. Gray; Andrew D.J. Pearson; Suzanne A. Eccles; Louis Chesler; Rani E. George
The ALK(F1174L) mutation is associated with intrinsic and acquired resistance to crizotinib and cosegregates with MYCN in neuroblastoma. In this study, we generated a mouse model overexpressing ALK(F1174L) in the neural crest. Compared to ALK(F1174L) and MYCN alone, co-expression of these two oncogenes led to the development of neuroblastomas with earlier onset, higher penetrance, and enhanced lethality. ALK(F1174L)/MYCN tumors exhibited increased MYCN dosage due to ALK(F1174L)-induced activation of the PI3K/AKT/mTOR and MAPK pathways, coupled with suppression of MYCN pro-apoptotic effects. Combined treatment with the ATP-competitive mTOR inhibitor Torin2 overcame the resistance of ALK(F1174L)/MYCN tumors to crizotinib. Our findings demonstrate a pathogenic role for ALK(F1174L) in neuroblastomas overexpressing MYCN and suggest a strategy for improving targeted therapy for ALK-positive neuroblastoma.
Cancer Discovery | 2015
Sarah L. Sawyer; Lei Tian; Kähkönen M; Jeremy Schwartzentruber; Martin Kircher; Jacek Majewski; Dyment Da; Innes Am; Kym M. Boycott; Lisa A. Moreau; Moilanen Js; Roger A. Greenberg
UNLABELLED Deficiency in BRCA-dependent DNA interstrand crosslink (ICL) repair is intimately connected to breast cancer susceptibility and to the rare developmental syndrome Fanconi anemia. Bona fide Fanconi anemia proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ), interact with BRCA1 during ICL repair. However, the lack of detailed phenotypic and cellular characterization of a patient with biallelic BRCA1 mutations has precluded assignment of BRCA1 as a definitive Fanconi anemia susceptibility gene. Here, we report the presence of biallelic BRCA1 mutations in a woman with multiple congenital anomalies consistent with a Fanconi anemia-like disorder and breast cancer at age 23. Patient cells exhibited deficiency in BRCA1 and RAD51 localization to DNA-damage sites, combined with radial chromosome formation and hypersensitivity to ICL-inducing agents. Restoration of these functions was achieved by ectopic introduction of a BRCA1 transgene. These observations provide evidence in support of BRCA1 as a new Fanconi anemia gene (FANCS). SIGNIFICANCE We establish that biallelic BRCA1 mutations cause a distinct FA-S, which has implications for risk counselling in families where both parents harbor BRCA1 mutations. The genetic basis of hereditary cancer susceptibility syndromes provides diagnostic information, insights into treatment strategies, and more accurate recurrence risk counseling to families.
Blood | 2012
Lars U.W. Müller; Michael D. Milsom; Chad E. Harris; Rutesh Vyas; Kristina Brumme; Kalindi Parmar; Lisa A. Moreau; Axel Schambach; In-Hyun Park; Wendy B. London; Kelly Strait; Thorsten M. Schlaeger; Alexander L. DeVine; Elke Grassman; Alan D. D'Andrea; George Q. Daley; David A. Williams
Fanconi anemia (FA) is a recessive syndrome characterized by progressive fatal BM failure and chromosomal instability. FA cells have inactivating mutations in a signaling pathway that is critical for maintaining genomic integrity and protecting cells from the DNA damage caused by cross-linking agents. Transgenic expression of the implicated genes corrects the phenotype of hematopoietic cells, but previous attempts at gene therapy have failed largely because of inadequate numbers of hematopoietic stem cells available for gene correction. Induced pluripotent stem cells (iPSCs) constitute an alternate source of autologous cells that are amenable to ex vivo expansion, genetic correction, and molecular characterization. In the present study, we demonstrate that reprogramming leads to activation of the FA pathway, increased DNA double-strand breaks, and senescence. We also demonstrate that defects in the FA DNA-repair pathway decrease the reprogramming efficiency of murine and human primary cells. FA pathway complementation reduces senescence and restores the reprogramming efficiency of somatic FA cells to normal levels. Disease-specific iPSCs derived in this fashion maintain a normal karyotype and are capable of hematopoietic differentiation. These data define the role of the FA pathway in reprogramming and provide a strategy for future translational applications of patient-specific FA iPSCs.