Effect of Fluorine Substitution on Absorption and Emission Properties of Figure-eight-shaped [5]Helicene Dimer: A Computational Study at RI-MP2/RI-ADC(2) Level.

Chirality is a very important characteristic of optically active molecules and polyaromatics with helical structures, and plays a vital role in various applications in material science. In the present work, we show the effects of fluorine substitution at various positions in a figure-8-shaped [5]helicene dimer on the ground and excited state g-factors. Calculations for the ground and excited states are performed at the MP2 and ADC(2) levels of theory, respectively. The results reveal that fluorination has a large effect on the excited state structures. The values of the excited state dissymmetry factors for the molecules with fluorinations at both ends of the figure-8 systems are smaller than that of the parent system. On the other hand, fluorinations only in the stacked-phenyl region results in an increase in the value of g cpl ${\left| {g_{{\rm{cpl}}} } \right|}$ . The perfluorinated system shows the smallest g cpl ${\left| {g_{{\rm{cpl}}} } \right|}$ .

Flap Endonuclease 1 Limits Telomere Fragility on the Leading Strand.

The existence of redundant replication and repair systems that ensure genome stability underscores the importance of faithful DNA replication. Nowhere is this complexity more evident than in challenging DNA templates, including highly repetitive or transcribed sequences. Here, we demonstrate that flap endonuclease 1 (FEN1), a canonical lagging strand DNA replication protein, is required for normal, complete leading strand replication at telomeres. We find that the loss of FEN1 nuclease activity, but not DNA repair activities, results in leading strand-specific telomere fragility. Furthermore, we show that FEN1 depletion-induced telomere fragility is increased by RNA polymerase II inhibition and is rescued by ectopic RNase H1 expression. These data suggest that FEN1 limits leading strand-specific telomere fragility by processing RNA:DNA hybrid/flap intermediates that arise from co-directional collisions occurring between the replisome and RNA polymerase. Our data reveal the first molecular mechanism for leading strand-specific telomere fragility and the first known role for FEN1 in leading strand DNA replication. Because FEN1 mutations have been identified in human cancers, our findings raise the possibility that unresolved RNA:DNA hybrid structures contribute to the genomic instability associated with cancer.

FEN1 ensures telomere stability by facilitating replication fork re-initiation.

Telomeres are terminal repetitive DNA sequences whose stability requires the coordinated actions of telomere-binding proteins and the DNA replication and repair machinery. Recently, we demonstrated that the DNA replication and repair protein Flap endonuclease 1 (FEN1) is required for replication of lagging strand telomeres. Here, we demonstrate for the first time that FEN1 is required for efficient re-initiation of stalled replication forks. At the telomere, we find that FEN1 depletion results in replicative stress as evidenced by fragile telomere expression and sister telomere loss. We show that FEN1 participation in Okazaki fragment processing is not required for efficient telomere replication. Instead we find that FEN1 gap endonuclease activity, which processes DNA structures resembling stalled replication forks, and the FEN1 interaction with the RecQ helicases are vital for telomere stability. Finally, we find that FEN1 depletion neither impacts cell cycle progression nor in vitro DNA replication through non-telomeric sequences. Our finding that FEN1 is required for efficient replication fork re-initiation strongly suggests that the fragile telomere expression and sister telomere losses observed upon FEN1 depletion are the direct result of replication fork collapse. Together, these findings suggest that other nucleases compensate for FEN1 loss throughout the genome during DNA replication but fail to do so at the telomere. We propose that FEN1 maintains stable telomeres by facilitating replication through the G-rich lagging strand telomere, thereby ensuring high fidelity telomere replication.

Flap endonuclease 1 contributes to telomere stability.

Telomere stability plays an important role in the preservation of genomic stability and is maintained through the coordinated actions of telomere-specific proteins and DNA repair and replication proteins [1, 2]. Flap endonuclease 1 (FEN1) is a protein that plays a role in lagging-strand DNA replication, base excision repair, homologous recombination, and reinitiation of stalled replication forks [3, 4]. Here, we demonstrate that FEN1 depletion leads to telomere dysfunction characterized by the presence of gammaH2AX and sister telomere loss. Expression of catalytically active telomerase, the reverse transcriptase that adds telomeric repeats to chromosome ends, was sufficient to rescue telomere dysfunction upon FEN1 depletion. Strikingly, FEN1 depletion exclusively abrogates telomeres replicated by lagging-strand DNA replication. Genetic rescue experiments utilizing FEN1 mutant proteins that retained the ability to localize to telomeric repeats revealed that FEN1's nuclease activity and ability to interact with the Werner protein (WRN) and telomere-binding protein (TRF2) were required for FEN1 activity at the telomere. Given FEN1's role in lagging-strand DNA replication and reinitiation of stalled replication forks, we propose that FEN1 contributes to telomere stability by ensuring efficient telomere replication.