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Роль и функции генов и белков BRCA1, BRCA2 и ATMВ патогенезе рака молочной железы
УДК:
614.2+575.191-616.006
Автор статьи:
Акильжанова А.Р.
Место работы автора:
РГП Национальный центр биотехнологии Республики Казахстан КН МОН РК
Название журнала:
Биотехнология. Теория и практика
Год выпуска:
2010
Номер журнала:
2
Страницы:
с.17-24
Резюме на казахском языке:
BRCA1 ж?не BRCA2 – ісікті тежейтін гендер, олардың мутантты фенотиптері сүт бездері мен аналық бездері қатерлі ісігінің дамуына бейімді. Қарқынды зерттеулер BRCA ақуыздарыныңкөптеген негізгі жасушалық үрдістерге қатысатындығын көрсетті. Екі ген де ДНҚ репарациясы мен ДНҚ зақымданғанда пайда болатын жауап кезіндегі транскрипциялық реттеуге қатысады.Жақында жүргізілген зерттеулердің н?тижесі BRCA ақуыздары хромосомалық тұрақтылықты сақтауға қажет, осылайша геномды зақымданулардан сақтайды деген болжамға келуге мүмкіндікбереді. Сонымен қатар, алынған н?тижелер BRCA ДНҚ репарациясына, жасушалық цикл ж?не апоптозға қатысатын кейбір гендерді реттейтінін көрсетеді. Осы функциялардың көбісі BRCA-мен өзара байланыста болатын, үлкен көлемдегі жасушалық ақуыздармен орындалады. BRCA ақуыздарының функциялары, сонымен қатар, белгілі бір фосфорлау үрдістерімен байланысты,бірақ молекулалық фосфарлаудың қандай жолы ісіктің дамуын тежейтін активтілікпен байланысты екенін анықтайтыны ?лі белгісіз. Қорыта келгенде, BRCA гендеріндегі мутациялардың сүт безі мен аналық безінің қатерлі ісігінің дамуына ?келетін себептері түсініксіз. BRCA гендерінің нақты молекулалық функцияларын зерттеу тұқымқуалайтын ж?не спорадикалық сүт безі қатерлі ісігінің патогенетикалық механизмдер ұғымын тереңірек түсінуге мүмкіндік береді.
Резюме на английском языке:
BRCA1 and BRCA2 are tumor suppressor genes, the mutant phenotypes of which predispose to breast and ovarian cancers. Intensive research has shown that BRCA proteins are involved in a multitude of pivotal cellular processes. In particular, both genes contribute to DNA repair andtranscriptional regulation in response to DNA damage. Recent studies suggest that BRCA proteins are required for maintenance of chromosomal stability, thereby protecting the genome from damage. Newdata also show that BRCAs transcriptionally regulate some genes involved in DNA repair, the cell cycle, and apoptosis. Many of these functions are mediated by a large number of cellular proteins that interactwith BRCAs. The functions of BRCA proteins are also linked to distinct and specifi c phosphorylation events; however, the extent to which phosphorylation-activated molecular pathways contribute totumor suppressor activity remains unclear. Finally, the reasons why mutations in BRCA genes lead to the development of breast and ovarian cancers are not clearly understood. Elucidation of the precisemolecular functions of BRCAs is expected to improve our understanding of hereditary as well as sporadic mammary carcinogenesis.
Список литературы:
1. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21 // Science 1990; 250: 1684–9.
2. WoosterR, NeuhausenSL, MangionJ,etal.Localization of a breast cancer susceptibility gene, BRCA2,to chromosome 13q12-13 // Science. - 1994. - 265-2088–90.
3. Wooster R, Bignell G, Lancaster J, et al. Identifi cation of the breast cancer susceptibility gene BRCA2// Nature. - 1995. – 378 - 789–92.
4. Rosen EM, Fan S, Pestell RG, Goldberg ID. BRCA1 gene in breast cancer // J Cell Physiol. – 2003.– 196 - 19–41.
5. Neuhausen SL, Marshall CJ. Loss of heterozygosity in familial tumors from three BRCA1-linkedkindreds // Cancer Res. – 1994. – 54 - 6069–72.
6. Rahman N, Stratton MR. The genetics of breast cancer susceptibility // Annu Rev Genet. – 1998. – 32- 95–121.
7. Ford D, Easton D, Bishop D et al. Consortium BCL. Risk of cancer in BRCA1-mutation carriers //Lancet. – 1994. - 343 - 592-5.
8. Ford D, Easton D, Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA l and BRCA 2 genes in breast cancer families. AmJ Hum Genet. – 1998. – 62 - 676-89.
9. Williams W, Anderson D. Genetic epidemiology of breast cancer, analysis of 200 Danish pedigrees // Genet Epidem. – 1984. – 1 - 7-20.
10. Couch F.J., et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer // N. Engl. J. Med. – 1997. – 336 - 1409-1415.
11. Sato T, Akiyama F, Sakamoto G et al. Accumulation of genetic alterations and progression of primary breast cancer // CancerRes. – 1991. – 51 - 5-94.
12. Jensen R, Thompson M et al. BRCA 1 is increted and exhibit properties of a granin // Nat Genet. – 1996. – 12 - 303-8.
13. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1 // Science. - 1994. – 266 - 66–71.
14. Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage // Cancer Sci. – 2004. – 95:11 – 866-873.
15. Scully R, Chen J, Ochs RL, et al. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage // Cell 1997; 90: 425–35.
16. Thomas JE, Smith M, Tonkinson JL, et al. Induction of phosphorylation on BRCA1 during the cell cycle and after DNA damage // Cell Growth Differ. - 1997; 8: 801–9.
17. Cortez D, Wang Y, Qin J, Elledge SJ. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 1999; 286: 1162–6.
18. Gatei M, Scott SP, Filippovitch I, et al. Role for ATM in DNA damage-induced phosphorylation of BRCA1. Cancer Res 2000; 60: 3299–304.
19. Gatei M, Zhou BB, Hobson K, et al. Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specifi c antibodies. J Biol Chem 2001; 276: 17276–80.
20. Chaturvedi P, Eng WK, Zhu Y, et al. Mammalian Chk2 is a downstream effector of the ATMdependent DNA damage checkpoint pathway.Oncogene 1999; 8: 4047–54. Bell DW, Varley JM, Szydlo TE, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome // Science. - 1999; 286: 2528–31.
21. Scully R, Chen J, Plug A, et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells // Cell. - 1997; 88: 265–75.
22. Chen J, Silver DP, Walpita D, et al. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells // Mol Cell. - 1998; 2: 317–28.
23. Sung P. Catalysis of ATP-dependent homologous DNA pairing and strand exchange by yeast RAD51 protein // Science. - 1994; 265: 1241–3.
24. Baumann P, Benson FE, West SC. Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro // Cell. - 1996; 87: 757–66.
25. Zhong Q, Chen CF, Li S, et al. Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response // Science. - 1999; 285: 747–50.
26. Wang Y, Cortez D, Yazdi P, et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures // Genes Dev. - 2000; 14: 927–39.
27. Wu X, Petrini JH, Heine WF, et al. Independence of R/M/N focus formation and the presence of intact BRCA1 // Science. - 2000; 289: 11.
28. Haber JE. The many interfaces of Mre11. Cell 1998; 95: 583–6.
29. Paull TT, Cortez D, Bowers B, et al. Direct DNA binding by Brca1. Proc Natl Acad Sci USA 2001; 98: 6086–91.
30. Yu VP, Koehler M, Steinlein C, et al. Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation // Genes Dev. - 2000; 14: 1400–6.
31. Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks // Mol Cell. - 2001; 7: 263–72.
32. Davies AA, Masson JY, McIlwraith MJ, et al. Role of BRCA2 in control of the RAD51 recombination and DNA repair protein // Mol Cell. - 2001; 7: 273–82.
33. Scully R, Chen J, Plug A, et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells // Cell. – 1997. – 88- 265–75.
34. Davies AA, Masson JY, McIlwraith MJ, et al. Role of BRCA2 in control of the RAD51 recombination and DNA repair protein // Mol Cell. - 2001. – 7 - 273–82.
35. Venkitaraman AR. Functions of BRCA1 and BRCA2 in the biological response to DNA damage // J Cell Sci. - 2001; 114: 3591–8.
36. Gatei M, Scott SP, Filippovitch I, et al. Role for ATM in DNA damage-induced phosphorylation of BRCA1 // Cancer Res. – 2000. – 60 - 3299–304.
37. Gatei M, Zhou BB, Hobson K, et al. Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessmentusing phospho-specifi c antibodies // J Biol Chem. – 2001. – 276 - 17276–80.
38. Chaturvedi P, Eng WK, Zhu Y, et al. Chk2 is a downstream effector of the ATM-dependent DNAdamage checkpoint pathway // Oncogene. – 1999. – 18 - 4047–54.
1. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21 // Science 1990; 250: 1684–9.
2. WoosterR, NeuhausenSL, MangionJ,etal.Localization of a breast cancer susceptibility gene, BRCA2,to chromosome 13q12-13 // Science. - 1994. - 265-2088–90.
3. Wooster R, Bignell G, Lancaster J, et al. Identifi cation of the breast cancer susceptibility gene BRCA2// Nature. - 1995. – 378 - 789–92.
4. Rosen EM, Fan S, Pestell RG, Goldberg ID. BRCA1 gene in breast cancer // J Cell Physiol. – 2003.– 196 - 19–41.
5. Neuhausen SL, Marshall CJ. Loss of heterozygosity in familial tumors from three BRCA1-linkedkindreds // Cancer Res. – 1994. – 54 - 6069–72.
6. Rahman N, Stratton MR. The genetics of breast cancer susceptibility // Annu Rev Genet. – 1998. – 32- 95–121.
7. Ford D, Easton D, Bishop D et al. Consortium BCL. Risk of cancer in BRCA1-mutation carriers //Lancet. – 1994. - 343 - 592-5.
8. Ford D, Easton D, Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA l and BRCA 2 genes in breast cancer families. AmJ Hum Genet. – 1998. – 62 - 676-89.
9. Williams W, Anderson D. Genetic epidemiology of breast cancer, analysis of 200 Danish pedigrees // Genet Epidem. – 1984. – 1 - 7-20.
10. Couch F.J., et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer // N. Engl. J. Med. – 1997. – 336 - 1409-1415.
11. Sato T, Akiyama F, Sakamoto G et al. Accumulation of genetic alterations and progression of primary breast cancer // CancerRes. – 1991. – 51 - 5-94.
12. Jensen R, Thompson M et al. BRCA 1 is increted and exhibit properties of a granin // Nat Genet. – 1996. – 12 - 303-8.
13. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1 // Science. - 1994. – 266 - 66–71.
14. Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage // Cancer Sci. – 2004. – 95:11 – 866-873.
15. Scully R, Chen J, Ochs RL, et al. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage // Cell 1997; 90: 425–35.
16. Thomas JE, Smith M, Tonkinson JL, et al. Induction of phosphorylation on BRCA1 during the cell cycle and after DNA damage // Cell Growth Differ. - 1997; 8: 801–9.
17. Cortez D, Wang Y, Qin J, Elledge SJ. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 1999; 286: 1162–6.
18. Gatei M, Scott SP, Filippovitch I, et al. Role for ATM in DNA damage-induced phosphorylation of BRCA1. Cancer Res 2000; 60: 3299–304.
19. Gatei M, Zhou BB, Hobson K, et al. Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specifi c antibodies. J Biol Chem 2001; 276: 17276–80.
20. Chaturvedi P, Eng WK, Zhu Y, et al. Mammalian Chk2 is a downstream effector of the ATMdependent DNA damage checkpoint pathway.Oncogene 1999; 8: 4047–54. Bell DW, Varley JM, Szydlo TE, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome // Science. - 1999; 286: 2528–31.
21. Scully R, Chen J, Plug A, et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells // Cell. - 1997; 88: 265–75.
22. Chen J, Silver DP, Walpita D, et al. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells // Mol Cell. - 1998; 2: 317–28.
23. Sung P. Catalysis of ATP-dependent homologous DNA pairing and strand exchange by yeast RAD51 protein // Science. - 1994; 265: 1241–3.
24. Baumann P, Benson FE, West SC. Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro // Cell. - 1996; 87: 757–66.
25. Zhong Q, Chen CF, Li S, et al. Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response // Science. - 1999; 285: 747–50.
26. Wang Y, Cortez D, Yazdi P, et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures // Genes Dev. - 2000; 14: 927–39.
27. Wu X, Petrini JH, Heine WF, et al. Independence of R/M/N focus formation and the presence of intact BRCA1 // Science. - 2000; 289: 11.
28. Haber JE. The many interfaces of Mre11. Cell 1998; 95: 583–6.
29. Paull TT, Cortez D, Bowers B, et al. Direct DNA binding by Brca1. Proc Natl Acad Sci USA 2001; 98: 6086–91.
30. Yu VP, Koehler M, Steinlein C, et al. Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation // Genes Dev. - 2000; 14: 1400–6.
31. Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks // Mol Cell. - 2001; 7: 263–72.
32. Davies AA, Masson JY, McIlwraith MJ, et al. Role of BRCA2 in control of the RAD51 recombination and DNA repair protein // Mol Cell. - 2001; 7: 273–82.
33. Scully R, Chen J, Plug A, et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells // Cell. – 1997. – 88- 265–75.
34. Davies AA, Masson JY, McIlwraith MJ, et al. Role of BRCA2 in control of the RAD51 recombination and DNA repair protein // Mol Cell. - 2001. – 7 - 273–82.
35. Venkitaraman AR. Functions of BRCA1 and BRCA2 in the biological response to DNA damage // J Cell Sci. - 2001; 114: 3591–8.
36. Gatei M, Scott SP, Filippovitch I, et al. Role for ATM in DNA damage-induced phosphorylation of BRCA1 // Cancer Res. – 2000. – 60 - 3299–304.
37. Gatei M, Zhou BB, Hobson K, et al. Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessmentusing phospho-specifi c antibodies // J Biol Chem. – 2001. – 276 - 17276–80.
38. Chaturvedi P, Eng WK, Zhu Y, et al. Chk2 is a downstream effector of the ATM-dependent DNAdamage checkpoint pathway // Oncogene. – 1999. – 18 - 4047–54.
Электронный вариант:
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BRCA1 (ген восприимчивости рака молочной железы 1) и BRCA2 – гены, подавляющие опухоль, мутантные фенотипы которых предрасполагают к развитию рака молочной железы и яичников. Интенсивные исследования показали, что BRCA белки вовлечены во множество основных клеточных процессов. В частности, оба гена участвуют в репарации ДНК и транскрипционном регулировании в ответна повреждение ДНК. Результаты недавних исследований позволяют полагать, что BRCA белки необходимы для поддержания хромосомной стабильности, таким образом защищая геном от повреждений. Новые данные также показывают, что BRCA регулируют некоторые гены, вовлеченные в репарацию ДНК, клеточный цикл иапоптоз. Многие из этих функций запускаются большим количеством клеточных белков, взаимодействующихс BRCA. Функции BRCA белков также связаны с процессами определенного фосфорилирования, однакоопределить, какой путь молекулярного фосфорилирования соотносится с активностью подавления ростаопухоли, остается неясным. Наконец, причины, почему мутации в BRCA генах ведут к развитию раковыхзаболеваний молочной железы и яичников, не совсем понятны. Изучение точных молекулярных функцийBRCA генов позволит улучшить наше понимание патогенетических механизмов как наследственного, так испорадического рака молочной железы.
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