{"id":98030,"date":"2025-07-03T15:03:06","date_gmt":"2025-07-03T13:03:06","guid":{"rendered":"https:\/\/port.lukasiewicz.gov.pl\/?post_type=projects&p=98030"},"modified":"2026-01-16T09:32:17","modified_gmt":"2026-01-16T08:32:17","slug":"new-factors-regulating-cell-cycle-checkpoints-in-response-to-dna-damage-checktwo","status":"publish","type":"projects","link":"https:\/\/port.lukasiewicz.gov.pl\/en\/projekty-badawcze\/new-factors-regulating-cell-cycle-checkpoints-in-response-to-dna-damage-checktwo\/","title":{"rendered":"New factors regulating cell cycle checkpoints in response to DNA damage \u2013 CHECKTWO"},"content":{"rendered":"\t\t
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Project funded by the National Science Centre (NCN) under the \u201cOpus \u2013 21\u201d call<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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Project number:<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t

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Project value:<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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\n\t\t\t\t\t\t\t\t\t1,954,440.00 PLN\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t
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Funding amount:<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t

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Project implementation period:<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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\n\t\t\t\t\t\t\t\t\t01\/03\/2022 \u2013 28\/02\/2025\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t
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Project manager:<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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\n\t\t\t\t\t\t\t\t\tDr. Micha\u0142 Malewicz\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t
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Cellular DNA is constantly exposed to damage caused by various endogenous factors, such as reactive oxygen species generated as by-products of aerobic metabolism, as well as exogenous factors, for example high-energy radiation. To protect their genetic material, cells have developed a complex set of adaptive responses activated upon DNA damage, collectively referred to as the DNA Damage Response (DDR). Activation of the DDR involves coordinated initiation of DNA repair mechanisms, changes in chromatin configuration, alterations in gene expression (at the transcriptional, post-transcriptional, and translational levels), induction of programmed cell death, and cell cycle arrest (activation of checkpoints).<\/p>

Dysregulation of any aspect of the DDR can have catastrophic consequences, and it is now well established that a defective DDR is a strong factor promoting cancer development. Defects in cell cycle control following DNA damage are particularly problematic, as they can lead to acute cell death or aneuploidy (when mitosis is attempted in the presence of numerous DNA double-strand breaks), thereby threatening genome stability. Several cell cycle checkpoints are activated in response to DNA damage at specific stages: the G1 checkpoint, the intra-S checkpoint, and the G2\/M checkpoint. The G1 checkpoint is crucial, as its role is to halt the cell cycle in G1 phase, preventing replication of damaged DNA. This checkpoint is functionally dependent on the p53 protein and prevents collisions between the replication machinery and damaged DNA. Because the p53 gene is inactivated in more than half of all human cancers, such cells become dependent on other checkpoints to protect against genomic instability\u2014primarily the G2\/M checkpoint.<\/p>

Consequently, pharmaceutical companies devote substantial effort to developing effective and safe pharmacological inhibitors of the G2\/M checkpoint, targeting various effector proteins of this checkpoint (mainly kinases). Importantly, identification of additional proteins and mechanisms regulating the G2\/M checkpoint could significantly expand our understanding of the DDR and potentially open new avenues for targeted cancer therapies.<\/p>

We have recently identified two new proteins that regulate the G2\/M checkpoint: LZIC and LYAR. Both factors are evolutionarily conserved, yet neither has a clearly defined molecular function. Inactivation of LZIC in cell cultures leads to weakened induction of the late G2\/M checkpoint after irradiation, impaired signal transmission from DNA damage to the cell cycle machinery, and aneuploidy. In contrast, silencing LYAR using siRNA results in proper functioning of the late G2\/M checkpoint but impaired induction of the early, ATM-dependent G2\/M checkpoint.<\/p>

Within this project, we plan to determine how LZIC and LYAR regulate the induction and maintenance of G2\/M checkpoints at the molecular level. In addition, we will search for synthetic lethal interactions between LZIC\/LYAR and other DDR pathways that could be exploited in oncology to develop new targeted therapies. Finally, we will investigate the expression patterns of LZIC and LYAR in lung cancer, which is characterized by intrinsic genomic instability, assessing their usefulness as biomarkers in oncology. We expect that the experimental data obtained in this project will significantly broaden our understanding of the mechanisms of physiological and pathological DDR, as well as support diagnostic and therapeutic efforts in oncology.<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t","protected":false},"excerpt":{"rendered":"

Project funded by the National Science Centre (NCN) under the \u201cOpus \u2013 21\u201d call Project number: Project value: Funding amount: Project implementation period: Project manager: Cellular DNA is constantly exposed to damage caused by various endogenous factors, such as reactive oxygen species generated as by-products of aerobic metabolism, as well as exogenous factors, for example […]<\/p>\n","protected":false},"featured_media":80002,"menu_order":0,"template":"","format":"standard","meta":{"_acf_changed":false,"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","inline_featured_image":false,"footnotes":""},"categories":[],"grupy_badawcze":[618],"pozostale_projekty":[],"class_list":["post-98030","projects","type-projects","status-publish","format-standard","has-post-thumbnail","hentry","grupy_badawcze-grupa-badawcza-dynamiki-genomu"],"acf":{"nr_projektu":"UMO-2021\/41\/B\/NZ1\/03750","nazwa_projektu":"1,954,440.00 PLN","wartosc_dofinansowania":"1,954,440.00 PLN","tematyka_projektu":"01\/03\/2022 \u2013 28\/02\/2025","opis_projektu":"","kierownik_projektu":["Dr. Micha\u0142 Malewicz"],"grupa_badawcza":["Biology of Astrocytes Research Group"],"dofinanowanie":"National Science Centre","dofinansowanie":"Narodowe Centrum Nauki"},"publishpress_future_action":{"enabled":false,"date":"2026-04-21 16:36:00","action":"category","newStatus":"draft","terms":[],"taxonomy":"category","extraData":[]},"publishpress_future_workflow_manual_trigger":{"enabledWorkflows":[]},"_links":{"self":[{"href":"https:\/\/port.lukasiewicz.gov.pl\/en\/wp-json\/wp\/v2\/projects\/98030","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/port.lukasiewicz.gov.pl\/en\/wp-json\/wp\/v2\/projects"}],"about":[{"href":"https:\/\/port.lukasiewicz.gov.pl\/en\/wp-json\/wp\/v2\/types\/projects"}],"version-history":[{"count":4,"href":"https:\/\/port.lukasiewicz.gov.pl\/en\/wp-json\/wp\/v2\/projects\/98030\/revisions"}],"predecessor-version":[{"id":98037,"href":"https:\/\/port.lukasiewicz.gov.pl\/en\/wp-json\/wp\/v2\/projects\/98030\/revisions\/98037"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/port.lukasiewicz.gov.pl\/en\/wp-json\/wp\/v2\/media\/80002"}],"wp:attachment":[{"href":"https:\/\/port.lukasiewicz.gov.pl\/en\/wp-json\/wp\/v2\/media?parent=98030"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/port.lukasiewicz.gov.pl\/en\/wp-json\/wp\/v2\/categories?post=98030"},{"taxonomy":"grupy_badawcze","embeddable":true,"href":"https:\/\/port.lukasiewicz.gov.pl\/en\/wp-json\/wp\/v2\/grupy_badawcze?post=98030"},{"taxonomy":"pozostale_projekty","embeddable":true,"href":"https:\/\/port.lukasiewicz.gov.pl\/en\/wp-json\/wp\/v2\/pozostale_projekty?post=98030"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}