Alessandra Pelegrini

From Laboratório de Reparo de DNA

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-|BSc, <b>Biological Sciences</b>, <b>Universidade Federal do Rio Grande do Sul – UFRGS, (2001/2005)</b>.<br>MSc, <b>Celular and Molecular Biology</b>, <b>Universidade Federal do Rio Grande do Sul – UFRGS, (2006/2007)</b>.<br>PhD, <b>Celular and Molecular Biology</b>, <b>Universidade Federal do Rio Grande do Sul - UFRGS and Universidade de São Paulo – USP, ( 2007/2012)</b>.<br><br>Has experience in Cell Biology, Molecular Biology and Next Generation Sequencing (NGS) on the identification of causative mutations for Mendelian diseases related to DNA repair deficiencies. <br><br> The researcher has experience in cell and molecular biology, culture of human and animal cells, proteomics and mass spectrometry, microscopy and immunofluorescence, drug testing and cytotoxicity.<br> Research keywords: <b>Cancer</b>, <b>DNA repair,/b>, <b>Replicative stress</b>, <b>Genetic instability</b> and <b>Chemotherapy and Therapeutic resistance</b><br> [http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4463877A9 Lattes]. +|BSc, <b>Biological Sciences</b>, <b>Universidade Federal do Rio Grande do Sul – UFRGS</b>,(2001/2005).<br>MSc, <b>Celular and Molecular Biology</b>, <b>Universidade Federal do Rio Grande do Sul – UFRGS</b>, (2006/2007).<br>PhD, <b>Celular and Molecular Biology</b>, <b>Universidade Federal do Rio Grande do Sul - UFRGS and Universidade de São Paulo – USP</b>, ( 2007/2012).<br>Post-doctoral Fellowship, <b> Cancer Research Center of Toulouse – CRCT</b> (2016/2018)<br>Post-doctoral Fellowship in DNA Repair Lab - <b>Institute of Biological Sciences at University of São Paulo - USP</b> (2013 – Current)<br><br>The researcher has experience in cell and molecular biology, culture of human and animal cells, proteomics and mass spectrometry, microscopy and immunofluorescence, drug testing and cytotoxicity<br><br> Research keywords: <b>Cancer</b>, <b>DNA repair</b>, <b>Replicative stress</b>, <b>Genetic instability</b> and <b>Chemotherapy and Therapeutic resistance</b><br> [http://lattes.cnpq.br/4410437371278362 Lattes].
<b>Contato:</b> aleepelegrini[at]gmail.com <b>Contato:</b> aleepelegrini[at]gmail.com
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== Current Project == == Current Project ==
-===Genotypic and phenotypic characterization of xeroderma pigmentosum (XP), cockayne syndrome (CS) and trichothiodystrophy (TTD) patients in Brazil ===+Cancer is currently the leading cause of morbidity and mortality worldwide which it is characterized by abnormal and uncontrolled cell growth in addition to genetic instability. It is very likely that genetic instability accelerates and even possibly initiates the proliferation of cancer cells by favoring the emergence of variant cells. Indeed, alterations of genes involved in genome maintenance promote carcinogenesis. This process is predominantly generated in S phase, during the DNA synthesis and relies on a replication stress activated by oncogenes. During the replication, the fork can be stalled for several reasons, such as DNA damage, structured DNA, nucleotide depletion and encounters with the transcription machinery, characterizing replication stress. In this way, replication stress contributes to chromosomal instability since stalled forks may eventually collapse, producing a broken DNA end. Up until recently, the mechanisms leading to fork collapse were only described after prolonged exposition of DNA replication stress sources (24 hours) by Mus81 activity. However, we have been described a phenomenon in which DNA replication forks stalls in response to DNA replication stress and are rapidly converted into DSBs, which we refer to as rapid replication fork breakage (RRFB) and it is dependent of XPF and Artemis nucleases. In this project, i have investigated the role of that endonuclease and its partner, ERCC1, in interstrand crosslink (ICLs) repair and its evolvement in chemotherapy sensitivity. Since the ICLs may cause persistent fork stalling, the proposed objective for this research is understanding how the XPF-ERCC1 complex and each of these separate protein participate in DNA replication stress, exploring their roles from the regulation of fork collapse to repair mechanisms, and evaluating the importance of these early events in the development of genetic instability from chromosomal aberrations.
-Deficiencies in nucleotide excision repair lead to human disorders where patients+
-display photosensitivity and/or neurological problems, such as xeroderma pigmentosum+
-(XP), cockayne syndrome (CS) and trichothiodystrophy (TTD). Case reports and+
-genotypic descriptions of patients have been published worldwide, mainly in North+
-America, Europe, Africa and Japan. The follow up of these patients for decades and the study with these+
-cells led to the understanding of what is currently known about the molecular pathways and genetic+
-defects involved in the phenotypes of these syndromes. In Brazil, a few case-reports describe some patients+
-with these phenotypes, and genetic and molecular characterizations are scarce. With the possibility to+
-identify mutations directly by Next Generation Sequencing (NGS) technique, we initiated a project to+
-diagnose the mutations involved in these NER syndromes, mainly XP. Therefore, we also plan to investigate+
-the origins of these mutations and ancestries by the analysis of haplotypes with SNP-array assays.+
-<br>+
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-[[Image:lerner.jpeg|350px]]+
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-== Publications ==+== Articles Published in Scientific Journals ==
-Munford V*, <b>Castro LP*</b>, Souto R, Lerner LK, Vilar JB, Quayle C, Asif H, Schuch AP, de Souza TA, Ienne S,+Melo-Hanchuk TD, Slepick PF, Meirelles GV, Basei FL, Lovato DV, Granato DC, Pauletti BA, Domingues RR, Leme AFP, <b>Pelegrini AL</b>, Lenz G, Knapp S, Elkins JM and Kobarg J. NEK1 kinase domain structure and its dynamic protein interactome after exposure to Cisplatin. <u>Scientific Reports</u> 2017; 7: (5445) 1-13.<br>[https://www.nature.com/articles/s41598-017-05325-w Full Text]<br><br>
-Alves FIA, Moura LMS, Galante PAF, Camargo AA, Liboredo R, Pena SDJ, Sarasin A, Chaibub SC, Menck CFM+Filippi-Chiela EC, Thomé MP, Bueno e Silva MM, <b>Pelegrini AL</b>, Ledur PF, Garicochea B, Zamin LL, Lenz G. Resveratrol abrogates the temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the temozolomide-induced senescence in glioma cells. <u>BMC Cancer</u> 2013; 13: 147.<br> [https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-13-147 Full Text]<br><br>
-(2017). A genetic cluster of patients with variant xeroderma pigmentosum with two different founder+Lopez PL, Filippi-Chiela EC, Silva AO, Cordero EA, Garcia-Santos D, <b>Pelegrini AL</b>, Reder GM, Barbieri NL, Lenz G. Sensitization of glioma cells by x-linked inhibitor of apoptosis protein knockdown. <u>Oncology</u> 2012; 83: 75-82.<br>[https://www.karger.com/Article/FullText/337978 Full Text]<br><br>
-mutations. <u>British Journal of Dermatology.</u> 176 (5), 1270-1278. <br> [https://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.15084 Full Text] [https://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.15435 Highlighted Comment] <br><br>+<b>Pelegrini AL</b>, Moura DJ, Brenner BL, Ledur PF, Maques GP, Henriques JA, Saffi J, Lenz G. Nek1 silencing slows down DNA repair and blocks DNA damage-induced cell cycle arrest. <u>Mutagenesis</u> 2010; 25: 447-54.<br>[https://academic.oup.com/mutage/article-lookup/doi/10.1093/mutage/geq026 Full Text]<br><br>
-Pedroso JL, Munford V, Bastos AU, <b>Castro LP</b>, Marussi VHR, Silva GS, Arita JH, Menck CFM, Barsottini OG+Gerhardt D, Horn AP, Gaelzer MM, Frozza RL, Delgado-Cañedo A, <b>Pelegrini AL</b>, Henriques AT, Lenz G, Salbego C. Boldine: a potential new antiproliferative drug against glioma cell lines. <u>Invest New Drugs</u> 2009; 27, 517-25.<br> [https://dx.doi.org/10.1007/s10637-008-9203-7 Full Text]<br><br>
-(2017). LMNB1 mutation causes cerebellar involvement and a genome instability defect. <u>Journal of the+
-Neurological Sciences.</u> 379:249-252. <br> [https://www.sciencedirect.com/science/article/pii/S0022510X1730401X?via%3Dihub Full Text] <br><br>+
-Lerner LK, Francisco G, Soltys DT, Rocha CR, Quinet A, Vessoni AT, <b>Castro LP</b>, David TI, Bustos SO, Strauss+
-BE, Gottifredi V, Stary A, Sarasin A, Chammas R, Menck CF (2016). Predominant role of DNA polymerase eta+
-and p53-dependent translesion synthesis in the survival of ultraviolet-irradiated human cells. <u>Nucleic Acids+
-Research.</u> 45 (3), 1270-1280.<br> [https://academic.oup.com/nar/article/45/3/1270/2631187 Full Text]<br><br>+

Revisão atual

BSc, Biological Sciences, Universidade Federal do Rio Grande do Sul – UFRGS,(2001/2005).
MSc, Celular and Molecular Biology, Universidade Federal do Rio Grande do Sul – UFRGS, (2006/2007).
PhD, Celular and Molecular Biology, Universidade Federal do Rio Grande do Sul - UFRGS and Universidade de São Paulo – USP, ( 2007/2012).
Post-doctoral Fellowship, Cancer Research Center of Toulouse – CRCT (2016/2018)
Post-doctoral Fellowship in DNA Repair Lab - Institute of Biological Sciences at University of São Paulo - USP (2013 – Current)

The researcher has experience in cell and molecular biology, culture of human and animal cells, proteomics and mass spectrometry, microscopy and immunofluorescence, drug testing and cytotoxicity

Research keywords: Cancer, DNA repair, Replicative stress, Genetic instability and Chemotherapy and Therapeutic resistance
Lattes.

Contato: aleepelegrini[at]gmail.com


Current Project

Cancer is currently the leading cause of morbidity and mortality worldwide which it is characterized by abnormal and uncontrolled cell growth in addition to genetic instability. It is very likely that genetic instability accelerates and even possibly initiates the proliferation of cancer cells by favoring the emergence of variant cells. Indeed, alterations of genes involved in genome maintenance promote carcinogenesis. This process is predominantly generated in S phase, during the DNA synthesis and relies on a replication stress activated by oncogenes. During the replication, the fork can be stalled for several reasons, such as DNA damage, structured DNA, nucleotide depletion and encounters with the transcription machinery, characterizing replication stress. In this way, replication stress contributes to chromosomal instability since stalled forks may eventually collapse, producing a broken DNA end. Up until recently, the mechanisms leading to fork collapse were only described after prolonged exposition of DNA replication stress sources (24 hours) by Mus81 activity. However, we have been described a phenomenon in which DNA replication forks stalls in response to DNA replication stress and are rapidly converted into DSBs, which we refer to as rapid replication fork breakage (RRFB) and it is dependent of XPF and Artemis nucleases. In this project, i have investigated the role of that endonuclease and its partner, ERCC1, in interstrand crosslink (ICLs) repair and its evolvement in chemotherapy sensitivity. Since the ICLs may cause persistent fork stalling, the proposed objective for this research is understanding how the XPF-ERCC1 complex and each of these separate protein participate in DNA replication stress, exploring their roles from the regulation of fork collapse to repair mechanisms, and evaluating the importance of these early events in the development of genetic instability from chromosomal aberrations.



Articles Published in Scientific Journals

Melo-Hanchuk TD, Slepick PF, Meirelles GV, Basei FL, Lovato DV, Granato DC, Pauletti BA, Domingues RR, Leme AFP, Pelegrini AL, Lenz G, Knapp S, Elkins JM and Kobarg J. NEK1 kinase domain structure and its dynamic protein interactome after exposure to Cisplatin. Scientific Reports 2017; 7: (5445) 1-13.
Full Text

Filippi-Chiela EC, Thomé MP, Bueno e Silva MM, Pelegrini AL, Ledur PF, Garicochea B, Zamin LL, Lenz G. Resveratrol abrogates the temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the temozolomide-induced senescence in glioma cells. BMC Cancer 2013; 13: 147.
Full Text

Lopez PL, Filippi-Chiela EC, Silva AO, Cordero EA, Garcia-Santos D, Pelegrini AL, Reder GM, Barbieri NL, Lenz G. Sensitization of glioma cells by x-linked inhibitor of apoptosis protein knockdown. Oncology 2012; 83: 75-82.
Full Text

Pelegrini AL, Moura DJ, Brenner BL, Ledur PF, Maques GP, Henriques JA, Saffi J, Lenz G. Nek1 silencing slows down DNA repair and blocks DNA damage-induced cell cycle arrest. Mutagenesis 2010; 25: 447-54.
Full Text

Gerhardt D, Horn AP, Gaelzer MM, Frozza RL, Delgado-Cañedo A, Pelegrini AL, Henriques AT, Lenz G, Salbego C. Boldine: a potential new antiproliferative drug against glioma cell lines. Invest New Drugs 2009; 27, 517-25.
Full Text

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