RecQ-like proteins are a family of DNA helicases that are evolutionary conserved from prokaryotes to eukaryotes. A large amount of experimental evidence suggests these proteins have a major role in the maintenance of genome stability. In humans five RecQ like helicase have been identified (RecQL1, BLM, WRN, RecQL4, and RecQL5), three of which are associated with rare genetic disorders with sever chromosomal and developmental abnormalities, and an elevated predisposition to cancer. Among the disease associated RecQ-like helicases, BLM and WRN have been subject to extensive research, while our collective knowledge about the function of RecQL4 is still very limited. Similarly, little is known about the role of RecQL1 and RecQL5 in maintenance of genome integrity. In the past studies of Sgs1, the Saccharomyces cerevisiae homolog of RecQ, have been very informative regarding BLM function. Thus, here we sought to further investigate BLM, RecQL1, and RecQL4 by using yeast as a model. By constructing humanized yeast strains we evaluated the ability of these genes to complement defects observed in sgs1∆. In Chapter 2, our investigation led to the development of a novel chimeric system, which was able to complement some defects of the sgs1∆ strain. In Chapter 3, by taking advantage of this chimeric system, we evaluated 41 known BLM variants identified in the general human population. This study resulted in identification of six novel variants that completely impaired BLM function and three novel variants that partially impaired BLM function. In Chapter 4 we conducted multiple yeast 2-hybrid screens in search for novel protein-protein interaction for RecQL1 and RecQL4. We have identified two new putatively interacting partners for RecQL1 and three putatively interacting partners for RecQL4. In Chapter 5, functional characterization of RecQL1, BLM, RecQL4 and RecQL5 in yeast suggested genetic interaction between BLM and RecQL4 and RecQL5. Finally, in Chapter 6 a random mutagenesis screen of BLM has led to identification a mutation that impairs BLM function by disrupting the HRDC domain. This mutant suggests that the HRDC domain of BLM has an important role in proper functionality of this helicase.