Recombination at subtelomeres is regulated by physical distance, double-strand break resection and chromatin status.

Homologous recombination (HR) is a conserved mechanism that repairs broken chromosomes via intact homologous sequences. How different genomic, chromatin and subnuclear contexts influence HR efficiency and outcome is poorly understood. We developed an assay to assess HR outcome by gene conversion (GC) and break-induced replication (BIR), and discovered that subtelomeric double-stranded breaks (DSBs) are preferentially repaired by BIR despite the presence of flanking homologous sequences. Overexpression of a silencing-deficient SIR3 mutant led to active grouping of telomeres and specifically increased the GC efficiency between subtelomeres. Thus, physical distance limits GC at subtelomeres. However, the repair efficiency between reciprocal intrachromosomal and subtelomeric sequences varies up to 15-fold, depending on the location of the DSB, indicating that spatial proximity is not the only limiting factor for HR EXO1 deletion limited the resection at subtelomeric DSBs and improved GC efficiency. The presence of repressive chromatin at subtelomeric DSBs also favoured recombination, by counteracting EXO1-mediated resection. Thus, repressive chromatin promotes HR at subtelomeric DSBs by limiting DSB resection and protecting against genetic information loss.

Tracing the path of cancer initiation: the AA protein-based model for cancer genesis.

BACKGROUND: Cancer is a defiant disease which cure is still far from being attained besides the colossal efforts and financial means deployed towards that end. The continuing setbacks encountered with today's arsenal of anti-cancer drugs and cancer therapy modalities; show the need for a radical approach in order to get to the root of the problem. And getting to the root of cancer initiation and development leads us to challenge the present dogmas surrounding the pathogenesis of this disease. RESULTS: This comprehensive analysis brings to light the following points: (i) Cancer with its plethora of genetic and cellular symptoms could originate from one major event switching a cell from normalcy-to-malignancy; (ii) The switching event is postulated to involve a pathological breakup of a non-mutated protein, called here AA protein, resulting in the acquisition of new cellular functions present only in cancer cells; (iii) Following this event, DNA mutations begin to accumulate as secondary events to ensure perpetuity of cancer. Supporting arguments for this protein-based model come mainly from these observations: (i) The AA protein-based model reconciles together the clonal-and-stem cell theories into one inclusive model; (ii) The breakup of a normal protein could be behind the cancer-linked inflammation symptom; (iii) Cancer hallmarks are but adaptive traits, earned as a result of the switch from normalcy-to-malignancy. CONCLUSIONS: Adaptation of cancer cells to their microenvironment and to different anti-cancer drugs is deemed here as the ultimate cancer hallmark, that needs to be understood and controlled. This adaptive power of cancer cells parallels that of bacteria also known with their resistance to a large range of substances in nature and in the laboratory. Consequently, cancer development could be viewed as a backward walk on the line of Evolution. Finally this unprecedented analysis demystifies cancer and puts the finger on the core problem of malignancy while offering ideas for its control with the ultimate goal of leading to its cure.

DNA Mutations May Not Be the Cause of Cancer.

Cancer is the most challenging disease of our time with increasing numbers of new cases each year, worldwide. Great achievements have been reached in cancer research through deep sequencing which helped define druggable targets. However, the still-evolving targeted therapy suffers resistance suggesting that DNA mutations considered as drivers may not have a role in tumor initiation. The present work discusses the role of DNA mutations as drivers and passengers in cancer initiation and development. First, it is important to discern the role of these DNA mutations as initiating events causing cancer or as contributors crucial for the development of a tumor once it has initiated. Second, breast cancer shown here illustrates how identification of DNA mutations in cancerous cells has influenced our approach for anti-cancer drug design. The cancer trilogy we have reached and described as: initial drug; resistance/recurrence; drug/treatment combinations, calls for a paradigm shift. To design more effective cancer drugs with durable and positive outcome, future cancer research needs to move beyond the sequencing era and explore changes which are taking place in cancer cells at levels other than the DNA. Evolutionary constraints may be acting as a barrier to preserve the human species from being transformed and, for that matter, all multi-cellular species which can incur cancer. Furthermore, mutations in the DNA do occur and for a multitude of reasons but without necessarily causing cancer. New directions will draw themselves when more focus is given to the event responsible for the switch of a cell from normalcy to malignancy. Until then, targeted therapy will certainly continue to improve the outcome of patients; however, it is unlikely to eradicate breast cancer depicted here.

Identifying and Targeting the Cause of Cancer is Needed to Cure Cancer.

Cancer cells continue to challenge scientists and oncologists due to the phenomenon of resistance. Moreover, recurrence, as seen in many treated patients, shows that currently-used anti-cancer drugs are unable to prevent the development of new cancer cells harboring new mutations. The purpose of this paper is to try to answer some of the questions regarding why cancer arises and why evolution would naturally lead to the development of cancer. Providing answers to these questions may shed new light on cancer development and potential causes of cancer. This work demonstrates that (1) cancer hallmarks are a series of events that can be organized in three consecutive stages; (2) cancer may develop when cells seek immortality; (3) heterogeneity in tumors may be explained by cancer cells not following universal laws for division; (4) evolution may not have selected for cancer; (5) currently-used anti-cancer drugs, with telomerase and poly adenosine diphosphate ribose polymerase inhibition given as examples, show that we may not be on the right track, as these drugs are probably targeting molecular symptoms of tumors but not their cause; and (6) after an attempt to define the cause of cancer, the potentials of immunotherapy are discussed. Future anti-cancer drugs should be able to shrink the original tumor(s) and most importantly prevent the rise of new cancer cells in treated patients. In order to achieve this goal, new drugs must target the cause of cancer. Therefore, future research must focus on identifying potential causes of cancer common to all types of cancers. Finally, while immunotherapy holds great prospects for future cancer cure and prevention, global action is needed to reduce harmful substances known to contribute to the development of cancer in the environment.